Adaptive Antiviral Immunity

The innate response slows a viral infection within the first hours and shapes what follows, but it does not provide antigen-specific recognition, broad effector reach, or lifelong memory. Those are the contributions of the adaptive immune system. Adaptive responses take roughly a week to assemble on first encounter, deploy a specific antigen-binding receptor on each responding cell, and leave behind a long-lived memory pool that responds far faster and more powerfully on re-exposure. This memory architecture is the substrate on which every vaccine ultimately depends.

The two arms of adaptive immunity

The adaptive response splits into a humoral arm mediated by antibodies secreted by B-lineage plasma cells, and a cellular arm mediated by T lymphocytes. The humoral arm acts mainly on free virions in the extracellular environment, neutralising them before they enter cells; the cellular arm acts on virus-infected cells from inside, killing them before they release new virions.

Both arms originate from naïve lymphocytes that recirculate through secondary lymphoid organs (lymph nodes, spleen, Peyer’s patches), sampling antigen brought there by dendritic cells from the site of infection. On recognition of cognate antigen, the lymphocyte is activated, expands clonally, differentiates into effector cells, and (after the infection is cleared) leaves a small population of long-lived memory cells.

Lymphocyte development and the antigen receptor repertoire

The antigen-binding receptors of B and T cells are generated by somatic recombination of gene segments in developing lymphocytes, an arrangement discovered by Susumu Tonegawa (Nobel Prize 1987) and shared by both lineages.

V(D)J recombination

The receptor variable region is assembled from a small number of gene segments drawn from larger pools, joined by the recombinases RAG1 and RAG2 (recombination activating genes 1 and 2).

Locus	Gene segment pool
Immunoglobulin heavy chain	~45 V (variable), ~25 D (diversity), 6 J (joining) segments
Immunoglobulin κ light chain	~35 V, 5 J segments
Immunoglobulin λ light chain	~30 V, 4–7 J segments
T cell receptor β chain	~50 V, 2 D, 13 J segments
T cell receptor α chain	~50 V, ~60 J segments

Diversity arises from three multiplicative sources: combinatorial selection of V, D, and J segments; junctional diversity from imprecise joining and terminal deoxynucleotidyl transferase (TdT) addition of random nucleotides at the junctions; and heavy–light chain (or α–β) pairing. The estimated total potential B cell receptor repertoire before antigen encounter is around 10¹² unique specificities, and the T cell receptor repertoire is of the same order. Allelic exclusion ensures each lymphocyte expresses only one functional receptor of one specificity.

B cell development

B cells develop in the bone marrow. Pluripotent haematopoietic stem cells commit to the B lineage, rearrange their immunoglobulin genes, and undergo developmental checkpoints that test the functionality of each step. Self-reactive B cells are deleted or rendered anergic; non-functional rearrangements are eliminated. Surviving naïve B cells carry membrane immunoglobulin M (IgM) and IgD on their surface and exit the bone marrow into the recirculating lymphocyte pool.

T cell development and thymic selection

T cells develop in the thymus. Bone-marrow-derived thymocytes rearrange their T cell receptor genes and undergo two selection steps:

• Positive selection in the thymic cortex: only thymocytes whose T cell receptor recognises self-MHC with modest affinity survive. Those that fail to engage self-MHC die by neglect. This is the molecular basis of MHC restriction (the principle that a given T cell can only ever respond to peptides presented on the same MHC alleles it was selected against), demonstrated by Rolf Zinkernagel and Peter Doherty (Nobel Prize 1996).
• Negative selection in the thymic medulla: thymocytes whose T cell receptor binds self-peptide–self-MHC complexes with high affinity are deleted. This removes autoreactive cells before they reach the periphery. Intermediate-affinity self-reactive cells are diverted into the regulatory T cell (Treg) lineage and contribute to peripheral tolerance.

Only around 1 to 2 per cent of thymocytes pass both checkpoints and exit as mature naïve T cells. The vast majority die by apoptosis. The process is a stringent quality filter that generates a self-tolerant but pathogen-reactive repertoire.

α/β T cells dominate (recognising peptide–MHC); γ/δ T cells are a minority population enriched at epithelial surfaces (skin, gut, lung) and recognise non-classical ligands.

Antigen presentation and MHC restriction

T cells cannot recognise whole viral proteins directly. They see only short peptide fragments displayed on the surface of host cells by major histocompatibility complex (MHC) molecules. The pathway a peptide takes determines which class of MHC molecule presents it and therefore which T cell subset inspects it.

The MHC class I (endogenous) pathway

Every nucleated cell continuously samples the proteins it is making in its own cytoplasm, including viral proteins synthesised by an infecting virus:

1. Cytoplasmic proteins are tagged with ubiquitin and fed into the proteasome, a barrel-shaped multi-subunit protease that produces peptides of 8 to 11 amino acids. Under interferon stimulation, the proteasome is partly remodelled into the immunoproteasome, optimised for MHC class I peptides.
2. Peptides are transported into the endoplasmic reticulum (ER) by the transporter associated with antigen processing (TAP), a TAP1–TAP2 heterodimer in the ER membrane.
3. Inside the ER, nascent MHC class I heavy chains pair with β2-microglobulin and are loaded with peptide, assisted by the chaperones calnexin, calreticulin, ERp57, and the adaptor tapasin.
4. The loaded peptide–MHC class I complex traffics through the Golgi to the cell surface and is inspected by CD8+ cytotoxic T cells.

The MHC class I peptide groove is closed at both ends, which is why it accommodates only short peptides.

The MHC class II (exogenous) pathway

This pathway is restricted to professional antigen-presenting cells (APCs): principally dendritic cells, macrophages, and B cells.

1. Extracellular antigen is taken up by endocytosis, phagocytosis, or B cell receptor-mediated uptake.
2. The antigen is digested in increasingly acidic endosomes and lysosomes by cathepsins into peptides of 13 to 18 amino acids.
3. Nascent MHC class II molecules in the ER carry the invariant chain (Ii), which occupies the peptide-binding groove and prevents premature loading of endogenous peptides.
4. The invariant chain is progressively degraded in a late endosomal compartment to a fragment called CLIP (class II-associated invariant chain peptide).
5. The chaperone HLA-DM swaps CLIP for an antigenic peptide from the endosome.
6. The loaded peptide–MHC class II complex traffics to the cell surface and is inspected by CD4+ helper T cells.

The MHC class II groove is open at both ends, which is why it accommodates longer peptides.

Cross-presentation

A specialised dendritic cell subset called cDC1 (conventional dendritic cell type 1, marked by CD141 (BDCA3), XCR1, CLEC9A, and dependence on the transcription factors IRF8 and BATF3) can divert extracellularly acquired viral antigen into the MHC class I pathway. The antigen escapes from the endosome into the cytoplasm and enters the standard proteasome / TAP / MHC class I route. The result is CD8+ T cell priming against viruses that do not infect dendritic cells directly, including hepatitis B virus (which replicates only in hepatocytes) and many other tissue-tropic agents. Without cross-presentation, the cytotoxic T cell response would be limited to the small subset of viruses that infect dendritic cells.

Comparison

	MHC class I	MHC class II
Source of antigen	Cytoplasmic (endogenous)	Extracellular (exogenous)
Cells that present	All nucleated cells	Professional APCs only
Peptide length	8–11 amino acids	13–18 amino acids
Groove ends	Closed	Open
T cell inspecting	CD8+ cytotoxic	CD4+ helper
Loading chaperones	Calnexin / calreticulin / ERp57 / tapasin	Invariant chain / CLIP / HLA-DM

CD1 and non-classical MHC class Ib molecules (HLA-E, F, G) present lipid and a restricted set of peptide antigens to unconventional T cells. MHC class I downregulation by viruses to escape CD8+ T cell recognition is countered by NK cell missing-self killing, covered in the Innate antiviral immunity article.

CD4+ helper T cells

Naïve CD4+ T cells recognise viral peptides on MHC class II through the T cell receptor, with the CD4 co-receptor binding the conserved β2 domain of MHC class II and CD28 binding CD80 (B7-1) or CD86 (B7-2) for the co-stimulatory second signal. On activation, they polarise into one of several effector subsets depending on the cytokine context.

Subset	Polarising cytokines	Master transcription factor	Effector cytokines	Function
Th1	IL-12 (from cDC1, macrophages); IFN-γ	T-bet	IFN-γ, IL-2, TNF	Activates macrophages, drives antiviral cell-mediated immunity, supports CD8+ CTL responses, promotes IgG1 / IgG3 class switching
Th2	IL-4	GATA-3	IL-4, IL-5, IL-13	Helminth and allergic responses; IgE class switching
Th17	IL-6, IL-23, TGF-β	RORγt	IL-17, IL-22	Extracellular bacterial and fungal defence; mucosal barrier function
Tfh (T follicular helper)	IL-6, IL-21	Bcl-6	IL-21, CD40 ligand	Germinal centre B cell help, drives somatic hypermutation, affinity maturation, class switching
Treg (thymic and induced)	TGF-β; IL-2	FoxP3	IL-10, TGF-β	Restrains immune responses; maintains tolerance

Th1 dominates in most antiviral responses, with Tfh essential for high-affinity class-switched antibody. CD4+ T cells are sometimes called the conductors of the adaptive response because they license both the cytotoxic T cell programme and the B cell programme. The progressive depletion of CD4+ T cells in untreated HIV-1 infection disables both arms, explaining the characteristic spectrum of opportunistic infections in advanced AIDS.

CD8+ cytotoxic T cells

CD8+ T cells recognise viral peptides on MHC class I, with the CD8 co-receptor binding the conserved α3 domain. For naïve cell priming, CD28 must engage CD80 / CD86 on a mature dendritic cell (usually with CD4+ T cell licensing of the dendritic cell through CD40). Effector CTL killing of infected target cells does not require co-stimulation: peptide–MHC class I engagement alone suffices.

T cell epitopes preferentially come from relatively conserved internal and non-structural viral proteins, whereas neutralising antibody epitopes are usually on the variable surface glycoproteins. CTL responses therefore tend to be more cross-reactive between strains than antibody responses, and particular HLA class I alleles are associated with slow disease progression in chronic viral infection (HLA-B57 and HLA-B27 in HIV-1, presenting immunodominant Gag peptides that the virus has difficulty mutating away from).

CTL killing mechanism: effector CTLs form an immunological synapse with the target and release preformed granules containing perforin (which polymerises to form pores in the target cell membrane) and granzymes (serine proteases that enter through the pores and trigger caspase-mediated apoptosis). They also upregulate Fas ligand (FasL), which engages target-cell Fas (CD95) to assemble the death-inducing signalling complex (DISC), activate caspase-8, and trigger apoptosis through the extrinsic pathway.

In persistent infection where antigen exposure is sustained for months to years, CD8+ T cells progressively upregulate inhibitory receptors (PD-1, TIM-3, LAG-3) and lose effector function, a state called T cell exhaustion. Exhausted CTLs contribute to the failure of viral clearance in chronic HIV, hepatitis C, and hepatitis B, and they are the target of checkpoint inhibitor therapies (anti-PD-1 antibodies) now explored for chronic viral infection. The molecular biology of exhaustion is treated in the Viral immune evasion article.

B cell activation and antibody production

B cells respond to antigen through their surface immunoglobulin receptor. Unlike T cells, they recognise antigen in its native conformation; no MHC presentation is required.

T-dependent and T-independent activation

B cell activation requires two signals: B cell receptor cross-linking by antigen (Signal 1), and either CD4+ T helper help (T-dependent) or strong innate / repetitive-antigen co-stimulation (T-independent).

T-dependent activation is the dominant pathway for protein antigens, including all viral proteins. After B cell receptor cross-linking, the B cell internalises and processes the antigen and presents peptides on MHC class II to T follicular helper (Tfh) cells in the germinal centre of a draining lymph node. Tfh cells deliver help through CD40 ligand binding to B cell CD40 plus the cytokine IL-21. The B cell then undergoes clonal expansion, somatic hypermutation, affinity maturation, isotype class switching, and differentiation into long-lived memory B cells and plasma cells.

T-independent activation is reserved for antigens that can cross-link many B cell receptors without T help: bacterial capsular polysaccharides and viral capsid proteins on intact icosahedral particles. T-independent responses produce mainly IgM, generate limited memory, and class-switch poorly. This is why polysaccharide vaccines are weakly immunogenic in young children whose T cell help is immature, and why conjugate vaccines that link polysaccharide to a protein carrier (which engages T help) work much better in this age group.

Affinity maturation

In the germinal centre, antigen-binding B cells undergo somatic hypermutation: the enzyme activation-induced cytidine deaminase (AID) introduces point mutations in the rearranged immunoglobulin variable region at around 10⁻³ mutations per base pair per cell division (a million times the background rate). Mutated B cells re-enter the light zone, compete for antigen displayed on follicular dendritic cells, and compete for limited Tfh help. B cells whose mutated receptors bind antigen more strongly capture more antigen, present more peptide on MHC class II, receive more Tfh help, and survive preferentially. Iterative cycles of mutation and selection over one to three weeks raise the average affinity of the population by several orders of magnitude.

Class switching

The initial antibody secreted by an activated B cell is IgM, but class switching can substitute the constant region of the heavy chain for IgG, IgA, or IgE while preserving the variable region (and therefore the antigen specificity) unchanged. Class switching is a DNA recombination event at the immunoglobulin heavy chain locus, catalysed by AID. Which class the B cell switches to is determined by the cytokine context: IFN-γ (Th1 context) drives switching to IgG1 / IgG3; IL-4 (Th2) drives IgG4 and IgE; TGF-β and the mucosal cytokine context drive IgA.

Hyper-IgM syndrome illustrates the importance of these steps. X-linked CD40 ligand deficiency abolishes germinal centre formation; autosomal recessive AID deficiency abolishes hypermutation and class switching. Affected patients produce only low-affinity IgM and present with severe sinopulmonary infection, Pneumocystis pneumonia, persistent cryptosporidium, and disseminated cytomegalovirus.

The immunoglobulin classes

Class	Structure	Properties	Role
IgG	Monomer; subclasses IgG1, IgG2, IgG3, IgG4	The major antibody class in blood. Crosses the placenta from mother to fetus. Subclasses differ in complement-fixing capacity (IgG1 and IgG3 strongest) and phagocyte Fc binding	Principal mediator of protection against reinfection following most systemic viral infections; long-lived; continues to be synthesised for years after primary infection
IgM	Pentamer of five IgG equivalents, with ten Fab fragments and ten antigen-binding sites	Avid binder; formed early in the immune response and later replaced by IgG. The first immunoglobulin in the fetus from the second half of pregnancy. Does not cross the placenta	Specific IgM is diagnostic of recent or chronic infection. IgM against a particular virus in a newborn is indicative of intrauterine infection (the TORCH screening principle)
IgA	Dimer with four Fab fragments; on passing through epithelial cells acquires a J chain (secretory component) to become secretory IgA	Protease-resistant; the principal immunoglobulin on mucosal surfaces and in milk and colostrum	Resistance to infection of the respiratory, gastrointestinal, and urogenital tracts. Important for vaccines delivered by the oral or respiratory route
IgD	Found on the surface of B lymphocytes	Less than 1 per cent of total immunoglobulin	Function in immune defence not well defined
IgE	Produced by sub-epithelial plasma cells in the respiratory and intestinal tracts; bound to mast cells	Less than 1 per cent of total immunoglobulin	Binds allergens on mast cells, releasing histamine and serotonin

Antibody effector functions

A bound antibody can protect against viral infection through several mechanisms.

• Neutralisation. IgG and secretory IgA bind viral surface glycoproteins (envelope or capsid) and block receptor attachment, uncoating, or membrane fusion. This is the dominant mechanism for preventing infection of new cells. Neutralisation works on free virions in the extracellular space and is the protective mechanism most vaccines aim for.
• Antibody-dependent cellular cytotoxicity (ADCC). Once viral glycoproteins reach the surface of an infected cell, IgG binds them. The Fc portion of bound IgG is recognised by natural killer (NK) cell CD16 (FcγRIII), which triggers NK perforin and granzyme release. ADCC links the humoral and innate arms of defence.
• Complement fixation. Bound IgG (particularly IgG1 and IgG3) and IgM activate the classical complement pathway via C1q. The cascade deposits C3b on the target (opsonisation for phagocytes), produces the anaphylatoxins C3a and C5a (recruiting neutrophils), and assembles the membrane attack complex (MAC, C5b–C9), which lyses enveloped virions and infected cells.
• Mucosal secretory IgA. Acts at the portal of entry, blocking attachment and entry of virus at mucosal surfaces before it reaches the underlying tissue. This is why secretory IgA is the principal protective mechanism against respiratory and enteric viruses, and why mucosal vaccine routes (oral, intranasal) are more effective at eliciting it than parenteral routes.
• TRIM21 (intracellular antibody-mediated immunity). When antibody-coated virions reach the cytoplasm of a cell (after penetrating the endosomal membrane), the cytosolic Fc receptor TRIM21 (tripartite motif-containing protein 21) binds the Fc, ubiquitinates the complex, and targets it for proteasomal degradation. TRIM21 acts against non-enveloped viruses such as adenoviruses that successfully reach the cytoplasm despite being antibody-coated.

Cytokines in the adaptive response

Cytokines act as autocrine, paracrine, or endocrine signals between immune cells. A single cytokine can have multiple effects; different cytokines can produce similar effects through distinct pathways (redundancy that protects the system from single-gene failure). Cytokines have five recognised roles in the antiviral response:

1. Augmenting the response: TNF and IFN-γ upregulate MHC expression and activate CTLs.
2. Regulating the response: IL-4 and IL-5 drive antibody isotype switching; IL-12 polarises Th1 differentiation.
3. Suppressing the response: IL-10 from Treg cells suppresses IFN-γ and Th1 activity.
4. Direct antiviral activity: the interferons (covered in the Innate antiviral immunity article).
5. Paradoxically upregulating viral gene expression in some cases (a feature that contributes to immunopathology, treated in the Immunopathology article).

Recovery from viral infection

The clinical observation of viral infections in children with congenital immunodeficiencies is the cleanest natural demonstration of which immune component does what in human defence. Several patterns are exam-classic.

• Children with Bruton’s X-linked agammaglobulinaemia (no B cells, no antibody) recover from most viral infections and retain memory of them. This shows that the cellular arm alone is sufficient for clearance of most viruses, and that memory does not require antibody. The exception is persistent enteroviral central nervous system infection (chronic echovirus or coxsackievirus meningoencephalitis), which can only be controlled by antibody and is invariably fatal in these patients without immunoglobulin therapy.
• Children with DiGeorge syndrome (congenital athymic aplasia, no T cells) develop severe viral disease. The textbook example is giant-cell measles pneumonitis without rash: the virus replicates unchecked in the respiratory tract and produces fatal pneumonia, while the typical measles rash is absent because the rash itself is a T cell mediated phenomenon.
• The same patterns hold for acquired immunodeficiency syndrome (AIDS) in adults: the slow loss of CD4+ T cells produces a spectrum of viral, mycobacterial, and protozoal reactivations identical in character to the congenital T cell defects, scaled to the depth of CD4 depletion.
• Adults receiving immunosuppressive therapy (chemotherapy, corticosteroids, transplant conditioning, B cell-depleting biologics) recapitulate the same patterns: HCMV reactivation in solid-organ transplant, JC virus progressive multifocal leukoencephalopathy after natalizumab, hepatitis B reactivation under rituximab.

These reactivation syndromes are the subject of the Immunocompromised Patients topic.

Immunological memory

Memory is the feature that distinguishes adaptive from innate immunity and is the reason vaccines work. After a primary response is resolved, most effector cells die, but a small population persists long-term in three principal forms.

Long-lived plasma cells

A fraction of antigen-specific B cells differentiate into long-lived plasma cells that home to specialised niches in the bone marrow and continuously secrete antibody for years to decades without further antigen stimulation. Long-lived plasma cells maintain the steady-state serum IgG titres that protect against re-infection.

Memory B cells

Memory B cells persist in lymphoid tissue, carrying affinity-matured and class-switched B cell receptors. On re-exposure they rapidly differentiate into new plasma cells, producing a faster and higher-affinity antibody response than the primary.

Memory T cell subsets

Memory T cells are divided into three populations with different anatomical distributions and roles:

Subset	Surface markers	Location	Role
Central memory (TCM)	CCR7+, CD62L+	Recirculate through secondary lymphoid organs	Long-lived reservoir; on re-encounter, expand and differentiate into new effector cells
Effector memory (TEM)	CCR7–, CD62L–	Patrol blood and peripheral tissue	Immediate cytokine release and cytotoxicity on re-encounter
Tissue-resident memory (TRM)	CD103+, CD69+, CCR7–	Permanently resident in mucosal surfaces (lung, intestine, female genital tract) and skin	First responders to local re-infection; do not recirculate

TRM are particularly important for viral immunity because most viral infections enter through a mucosal or cutaneous surface. Circulating central or effector memory cells must be recruited from the blood, taking hours to days. TRM are already in the tissue at the moment of re-exposure and can contain replication within minutes. Skin TRM persist for years after primary varicella-zoster virus infection and contribute to suppression of viral reactivation; lung TRM are critical for heterosubtypic protection against influenza A; genital tract TRM are central to protection against herpes simplex virus type 2 recurrences. The recognition of TRM has driven much of the current interest in mucosal vaccine routes for respiratory and sexually transmitted viruses.

Immunity to reinfection

Most acute viral infections leave lifelong immunity to reinfection, mediated by serum IgG, mucosal IgA, and memory T cells. The rule has important exceptions.

Original antigenic sin is the phenomenon that immunological memory of the first encounter with a virus dominates subsequent responses to related but non-identical variants. When the host meets a drifted variant, pre-existing memory B cells against shared (cross-reactive) epitopes outcompete naïve B cells against new variant-specific epitopes, biasing the antibody response back towards the priming strain. The phenomenon was first described by Thomas Francis Jr in 1960 in the context of influenza, and is also documented for enteroviruses, reoviruses, paramyxoviruses, and togaviruses. Two clinically important contexts are influenza annual vaccine reformulation (the basis of the “imprinting” effect that partly explained the unusual age distribution of severe disease in the 2009 H1N1 pandemic) and sequential dengue infection (the cross-reactive but poorly-neutralising antibody from the first serotype enhances rather than neutralises the second; see the Immunopathology article on antibody-dependent enhancement).

Mucosal secretory IgA is relatively short-lived, which is one reason that respiratory and enteric viral reinfections are common despite high serum IgG titres against the same virus.

Antigenic variation (drift and shift in influenza, hypervariability in HIV envelope, dengue serotype diversity) is treated in the Viral immune evasion article.

Active and passive immunity

Immunity to a virus can be acquired in two fundamentally different ways. Active immunity is generated by the host’s own immune response; passive immunity is conferred by transferred pre-formed antibody.

Active immunity is produced by natural infection (which clears, leaves memory) or by vaccination (which mimics infection sufficiently to prime memory without causing disease). The major vaccine modalities and the memory compartments each engages are treated in the dedicated question in the Test Your Knowledge set for this article.

Passive immunity arises naturally through transplacental transfer of maternal IgG in the third trimester (protecting the newborn for six to twelve months), and through secretory IgA in colostrum and breast milk. It is provided therapeutically by pooled human immunoglobulin (HBIG for hepatitis B post-exposure prophylaxis, RIG for rabies, VZIG for varicella in pregnancy and immunocompromised hosts) and by monoclonal antibodies (palivizumab and nirsevimab for RSV; Inmazeb and ansuvimab for ebolavirus; ibalizumab for multidrug-resistant HIV).

The general rule is that passive immunity buys time while active immunity provides durability. Where the inoculum has already arrived and the active response cannot ramp up fast enough, combined active-plus-passive prophylaxis is used: rabies post-exposure prophylaxis (RIG infiltrated around the wound plus a four-dose vaccine series); hepatitis B prophylaxis of the newborn of an HBsAg-positive mother (HBIG within 12 hours plus the first vaccine dose within 24 hours).

Clinical correlates: when the adaptive arm fails

Specific defects in the adaptive arm produce specific patterns of viral disease.

• Severe combined immunodeficiency (SCID) (X-linked common gamma chain, JAK3, ADA, RAG1 / RAG2, others): no T cells, often no B cells. Fatal disseminated herpesvirus disease, severe reactions to live vaccines (BCG, oral polio, rotavirus, varicella), giant-cell measles pneumonitis without rash. Lethal without haematopoietic stem cell transplantation.
• DiGeorge syndrome (22q11.2 deletion, thymic aplasia): T cell deficiency with normal B cells. The textbook giant-cell measles pneumonitis without rash case.
• Bruton’s X-linked agammaglobulinaemia (BTK mutations): no mature B cells, no antibody. Recovery from most viral infections through CTL alone, but uniquely susceptible to persistent enteroviral CNS infection.
• Hyper-IgM syndrome (X-linked CD40 ligand deficiency, autosomal recessive AID deficiency): no class switching, only IgM. Severe sinopulmonary infection, Pneumocystis, cryptosporidium, disseminated CMV.
• Common variable immunodeficiency (CVID): a heterogeneous syndrome of low IgG and impaired antibody responses, presenting in adolescence or adulthood with recurrent sinopulmonary infection and chronic enteroviral infection.
• Bare lymphocyte syndrome type II: MHC class II expression defects; failure of CD4+ T cell development; combined immunodeficiency.
• TAP deficiency: MHC class I peptide loading failure; surprisingly mild viral susceptibility because of compensating NK and cross-presentation responses.

References and recommended reading

• Burrell CJ, Howard CR, Murphy FA. Adaptive Immune Responses to Infection. In: Fenner and White’s Medical Virology, 5th edition, Chapter 6. Academic Press / Elsevier; 2017. The principal source for lymphocyte development, antigen presentation and MHC restriction, the helper and cytotoxic T cell responses, antibody effector functions and immunological memory.
• Burton DR, Pillai S, Hahn YS, Braciale TJ. The Adaptive Immune Response to Viruses. In: Fields Virology, 7th edition, Chapter 10. Wolters Kluwer; 2023. Current coverage of cross-presentation by cDC1, tissue-resident memory T cells, broadly neutralising antibodies and germline-targeting vaccine strategies, and CD8 T cell exhaustion.
• Sompayrac LM. How the Immune System Works, 6th edition. Wiley-Blackwell; 2019. Plain-language explanations of MHC antigen presentation, germinal-centre biology and vaccine modalities.