| Mucosal vs. Systemic Immunity | Mucosal Immunity | Systemic Immunity | References |
| Location and Role | Mucosal surfaces in nasal, oral, and lower respiratory tracts act as primary barriers. Interferons and immune cells in the airway can suppress replication and prevent spread to lungs. Successful mucosal responses can result in asymptomatic or mild infection and reduced transmission. | Circulates in blood and lymph. Systemic effectors (antibodies, T cells) disperse throughout the body to eliminate virus and protect vital organs. Key for preventing viremia and severe disease dissemination. Systemic responses typically react after infection is established, highlighting need for mucosal containment. | |
| Epithelial Cells | Airway and alveolar epithelial cells are the first line of defense against infection and also act as immune mediators. They produce IFN-λ (Type III IFN), inducing antiviral states without excessive inflammation (i.e. cytokine storm associated with systemic INFs). Epithelial cells also release chemokines (e.g. CCL2, CXCL10) to recruit immune cells (e.g. monocytes, neutrophils, and lymphocytes) to the mucosa. Additionally, epithelial cells can secrete alarmins (IL-33, IL-25, TSLP) upon damage to activate innate lymphoid cells and amplify mucosal immunity. They contribute to the formation of iBALT by producing CXCL13/CCL19/21 in concert with dendritic cells. Some coronaviruses (SARS-CoV-1, MERS-CoV, SARS-CoV-2) suppress epithelial IFN production early; individuals who overcome this suppression (e.g. children) are more likely to control infection. | Systemically, epithelial-derived antiviral factors can be detected indirectly. If the infection goes systemic, organ and blood vessel-resident epithelial cells can produce Type I INFs (IFN-α/β) and pro-inflammatory cytokines, contributing to systemic inflammation. However, measuring epithelial cytokines in blood is not straightforward; instead, surrogate markers are used (e.g. ISG products). For example, IFN-induced phospholipid scramblase 1 (PLSCR1) expression in blood may indicate epithelial antiviral readiness. | |
| Dendritic Cells | Mucosal dendritic cells secrete IL-12, IL-6 to promote Th1/Th17 responses, enhancing barrier defense and antiviral immunity. Dendritic cells in the respiratory tract also help form inducible bronchus-associated lymphoid tissue (iBALT) by producing homeostatic chemokines (CCL19/21, CXCL13) that organize lymphocytes locally. | Systemically, conventional dendritic cells in lymph nodes and spleen orchestrate T-cell and B-cell priming after infection or vaccination. In mild infection or effective vaccination, dendritic cells mature and present antigen robustly, leading to strong Th1 responses. However, in severe COVID-19, SARS-CoV-2 has been noted to impair dendritic cell maturation. Targeted dendritic cell vaccines or adjuvants can enhance systemic dendritic cell function. | |
| IgA | Mucosal secretory IgA (sIgA) binds spike protein to block epithelial attachment and promotes "immune exclusion" in mucus. Locally produced by IgA⁺ plasma cells in submucosa, supported by TGF-β, BAFF, APRIL cytokines. Critical for preventing reinfection at entry. Elevated nasal and oral sIgA correlates with reduced viral load and transmission. Short half-life but can be rapidly re-induced upon re-exposure. | Serum-specific IgA may indicate mucosal immune activation but is not protective at entry points. Circulating IgA lacks the secretory component and is often a “spillover” into mucosa without efficient transport. | |
| IgG | Some IgG is present in mucosal tissues (via local plasma cells or transudation), especially after infection or intranasal vaccination. Mucosal IgG levels from IM vaccination alone are relatively low, increasing substantially if preceded by infection (hybrid immunity). Levels can also be increased significantly by boosting. In lungs, tissue-resident plasma cells can secrete IgG during convalescence, contributing to local immunity. Mucosal IgG contributes to local memory post-infection or mucosal vaccination. | IgG in circulation is the predominant long-lived neutralizing antibody, conferring durable protection against systemic spread and severe disease. Blocks viral spread to organs, opsonizes virus for phagocytes, and activates complement/ADCC. Vaccine-induced IgG is typically high-titer and sustained, but it distributes less well into the mucosa than IgA. IgG memory B cells are abundant in blood and spleen, enabling rapid boost of antibody levels upon re-infection or boosting. | |
| B-cell Activation and Class Switching | Mucosal B-cell activation often occurs in tonsils or bronchial lymphoid aggregates. Local dendritic cells and epithelial signals (TGF-β, BAFF, APRIL, CXCL13, etc.) drive class-switching to IgA in mucosal lymphoid tissues. Mucosal-associated invariant T (MAIT) and other T cells in the mucosa also help drive IgA switching (via IL-17, IL-21, CD40L). Results in IgA⁺ plasmablasts homing to mucosa. Mucosal germinal center reactions are critical for secretory IgA quality. Mucosal prime boosting can convert systemic IgG-producing B cells to mucosal IgA-producers. | Systemic BAFF/APRIL act in tandem with IL-21 from Tfh to promote B-cell maturation and class switching (primarily to IgG) in lymph nodes and the spleen. Systemic B-cell activation yields circulating plasmablasts that home to bone marrow or inflamed tissues to become plasma cells. Class switching to IgG is dominant; IgM response occurs early and transitions to high-affinity IgG. Memory B cells persist in blood and bone marrow for long-term antibody production. | |
| Memory B Cells | Reside in mucosal tissues; rapidly produce IgA upon re-exposure. Though B cells are relatively scarce in healthy lung tissue, infection can establish local IgA⁺ memory B cells that rapidly mobilize in subsequent infections. Memory B cell populations in the mucosa wane with age, contributing to reduced local immunity in older patients. Ipsilateral boosting (same lymph nodes as prime dose) and Prmt1 and Cr2 expression is associated with germinal center activity, while contralateral boosting and Egr1 and Bhlhe40 expression is associated with plasma cell differentiation. | Circulating memory B cells are detectable in blood. They circulate through blood and reside in spleen, lymph nodes, and bone marrow niches. They persist after infection or vaccination and can quickly differentiate into IgG-secreting plasmablasts upon reinfection or boosting. Systemic memory B cells (often Spike-targeted) can adapt to variant exposure with help from Tfh cells. Systemic memory B cells are longer-lived than mucosal memory B cells, persisting for years, though their specificity may be focused on the initial strain (original antigenic imprinting). In children, memory B cells are broad but shorter-lived; in adults, they are narrower but more long-lived. | |
| Tissue-Resident Memory (TRM) T Cells | Antigen-specific TRMs in nasal and lung tissues provide rapid localized immunity and reduce reinfection risk. | Precursors detectable in circulation, though less abundant than in the mucosa; systemic vaccines induce fewer TRMs. | |
| Tfh Cells & Germinal Centers | Mucosal Tfh cells in respiratory lymphoid tissue guide local B cells to produce IgA. MAIT cells and dendritic cells in mucosa enhance Tfh generation (e.g. via IL-6, IL-23). Tfh-derived IL-21 and CD40L in bronchial germinal centers drive IgA class switch and somatic hypermutation. If mucosal Tfh support is suboptimal (e.g. in older age), IgA responses are impaired. | Systemic Tfh cells in lymph nodes/spleen are central to robust IgG responses. They reside in germinal centers of secondary lymphoid organs, providing help to B cells for affinity maturation. Strong systemic Tfh responses correlate with high-affinity, durable antibody production after vaccination. Impairment of Tfh (due to age or severe infection) leads to reduced antibody quantity and quality. Diverse Tfh clones from natural infection can broaden antibody repertoires, aiding recognition of variants. Circulating Tfh (cTfh) in blood can serve as a proxy for germinal center activity; reduced cTfh activation in severe disease or in elderly patients correlates with weaker antibody responses. | |
| CD4⁺ T Cells (Th1/Th17 and Treg) | Th1 cells at mucosa produce IFN-γ and TNF to activate macrophages and support CD8/NK function, critical for viral control. Mucosal Th17 cells (IL-17 producers) recruit neutrophils and enhance barrier defense, contributing to viral clearance, especially at epithelial surfaces. Some studies have indicated that excessive accumulation of CD4⁺ cells in lungs (e.g., too many TRM or Th17) can worsen inflammation (implicated in ARDS). Tregs (FOXP3⁺, ENTPD1⁺) may increase locally in severe disease, dampening protective immunity. | Circulating CD4⁺ T cells coordinate systemic immunity. Th1 polarization systemically is associated with better control of disseminated virus and is often promoted by vaccination. Th1 cells decline in severe cases, contributing to systemic immune imbalance; cytotoxic CD4⁺ T cells (CD4-CTLs) expand in hospitalized patients (perhaps to compensate for poor CD8⁺ function) and may mediate both viral clearance and immunopathology. In critical illness, conventional Th1 cells are often decreased in frequency, and many CD4⁺ T cells acquire an “exhausted” or abnormal phenotype. Circulating CD4⁺ Tfh cells are less activated in the elderly or severe patients, impairing antibody responses. Systemic Tregs typically maintain immunological homeostasis; an imbalance (too few) could mean hyperinflammation, whereas too many (or too suppressive) could hinder viral clearance. | |
| CD8⁺ T Cells | CD8⁺ TRMs (GZMK⁺, IFN-γ⁺) in nasal/lung tissues mediate local control; cytotoxic but not overly inflammatory (focused release of perforin/granzymes). Presence of CD8⁺ TRMs in the lungs is particularly correlated with lower viral loads and improved protection. Mucosal CD8 responses are less prone to exhaustion during mild infection (if antigen is cleared). However, if viral antigen persists at mucosa (chronic inflammation), they can become functionally impaired. | Circulating CD8⁺ T cells are crucial for systemic viral clearance and recovery. They kill virus-infected cells presenting viral peptides on MHC I. Loss of circulating CD8⁺ T cells is associated with critical illness. Circulating CD8 effectors (GNLY⁺, GZMK⁺) become exhausted in severe disease (PD-1⁺, LAG3⁺, CTLA4⁺), limiting viral control. Memory CD8⁺ T cells formed systemically can reside long-term in bone marrow for rapid response upon reinfection. | |
| MAIT Cells | MAIT cells are enriched in mucosal tissues and respond rapidly via innate-like recognition. During acute infection, MAIT cells migrate from blood to lungs (blood levels drop). They activate dendritic cells via CD40L and promote Tfh differentiation, enhancing mucosal antibody (IgA) responses. They also produce IL-17 and IFN-γ, contributing to the antiviral response. MAIT cells have some cytotoxic capability and can kill infected cells or limit inflammation. In moderate infection, MAIT cells exhibit an activated phenotype (CD38⁺ HLA-D⁺), correlating with mucosal defense, but in severe cases they exhibit signs of exhaustion (PD-1^) and functional impairment. | Peripheral MAIT cell frequency and activation status mirror mucosal activity. However, in circulation, MAIT cells comprise a small fraction of T cells. During acute disease, peripheral MAIT cell counts drop as they migrate to infected tissues. Systemically, MAIT cells can contribute by releasing inflammatory cytokines (IFN-γ, TNF) that support a systemic antimicrobial state, but in viral infections their main role is supporting other immune cells. MAIT frequency and function decline with age and can be suppressed in comorbid conditions, which might partly explain weaker mucosal vaccine responses in these patient populations (i.e., MAIT support to B cells/Tfh is reduced). | |
| Unconventional T Cells | Tissue γδ T cells in the lung act as a first responder subset. They recognize stressed/infected cells via non-peptide antigens and quickly secrete IL-17, IFN-γ, and TNF-α. They can also directly kill infected epithelial cells via cytotoxic granule release. NKT cells (CD56⁺, CD160⁺) expand in moderate mucosal responses, but Tim-3⁺ NKT associate with severity. They can respond to glycolipid antigens and secrete a mix of Th1/Th2 cytokines rapidly. | γδ T cells are depleted in blood during acute infection. The systemic role of γδ T cells includes immunosurveillance for infected or stressed cells throughout the body. NKT expansion in moderate disease is replaced by exhausted subsets in severe disease. Systemic NKT cells can respond to dendritic cell signals and help bias immune responses. | |
| NK Cells | Mucosal NK cells patrol the airway and are among the first responders to infected cells. They recognize infected epithelial cells via stress ligands and the absence of “self” (MHC I) signals, and kill them by releasing perforin and granzymes, curbing local viral replication. Mucosal NKs also secrete IFN-γ, which amplifies local antiviral defenses and modulates adaptive immunity. In the airway mucosa, NK cells act early to limit viral spread; experimental in vivo depletion of NK cells leads to higher lung viral loads and prolonged shedding. Mucosal NKs are activated (upregulating activation receptors like NKG2C) in mild/moderate infection, providing cytotoxic control without excessive inflammation. This is aided by the tissue environment which provides survival factors (IL-15) for NKs. | Circulating NK cells provide systemic surveillance and contribute to viral clearance. In early infection, some blood NK cells move into the lungs (contributing to the drop in peripheral NK count often seen in COVID-19). Those remaining in blood can kill any infected cells (e.g. virally infected endothelial cells or others) that they encounter and secrete cytokines (e.g. IFN-γ and GM-CSF) to shape the immune response. In severe disease, peripheral NK cell counts often drop, and remaining NKs can show signs of exhaustion (e.g. Tim-3⁺, PD-1⁺) in severe disease. Such dysfunction may allow greater viral spread and also fail to regulate macrophages (normally NK IFN-γ supports the antiviral state of macrophages). | |
| Proinflammatory Cytokines (e.g. IL-6, IL-8, IL-1β, TNF-α, IFN-γ) | Secreted in mucosa to attract leukocytes and enhance innate antiviral activity. IL-1β and TNF from mucosal macrophages and epithelial cells increase vascular permeability and leukocyte recruitment to infected mucosa. IL-8 from epithelial cells attracts neutrophils to phagocytose virus and debris. IFN-γ from mucosal NK and T cells directly inhibits viral replication and activates macrophages. In mild infections, nasal fluids contain high IFN-γ, IL-1β, and IL-8, suggesting a rapid, regulated mucosal cytokine response. | Serum cytokines may reflect systemic inflammation or correlate with clinical outcomes. In severe COVID-19, elevated serum IL-6, IL-8, IL-1β, TNF and others indicate a cytokine storm that correlates with organ damage. High serum IL-6 and IL-1β correlate with fever, acute phase protein release, and pathological inflammation (e.g. capillary leak leading to ARDS). Elevated IL-8 systemically drives neutrophils into circulation and tissues, contributing to tissue damage. IFN-γ in the bloodstream is typically lower or delayed in severe cases (impaired Th1 response), whereas a balanced early IFN-γ elevation is associated with effective viral control and milder outcomes. | |
| Lymphoid Chemokines (e.g. CXCL13, CCL19, CCL21) | Organize immune cell trafficking in tissues, and promote iBALT formation, enhancing localized adaptive responses. Mucosal dendritic cells and stromal cells produce CXCL13 to attract Tfh and B cells, promoting germinal center formation in tissues. This leads to iBALT development in lungs during infection which supports localized antibody production (especially IgA) and TRM formation. CCL19/CCL21 recruit naive and central memory T cells to mucosal lymphoid aggregates and guide dendritic cell migration. | Elevated levels in serum may reflect lymphoid tissue activation, indicating ongoing germinal center reactions or severe infection driving extrafollicular responses. In acute disease, higher plasma CXCL13 has been associated with ongoing germinal center activity and higher neutralizing Ab titers. However, very high CXCL13 might indicate aberrant lymphoid neogenesis or severe infection, driving extrafollicular B-cell activation. Increased CCL19 and CCL21 in blood may indicate mobilization of T and B cells (as seen after some vaccines or in systemic inflammation). | |
| Immune Imprinting | Mucosal responses shaped by initial antigen exposure; imprinting can limit adaptability to new variants. Local memory B and T cells (though T-cell responses are less prone to imprinting) preferentially target epitopes from the original strain of the virus, which can reduce the response to novel epitopes on a variant strain. Repeated exposure can broaden immunity over time (i.e., affinity maturation). | Repeat exposure improves affinity but may constrain breadth; systemic imprinting affects booster responsiveness. Systemic T-cell responses are less susceptible to imprinting (T-cell epitopes are often more conserved). Strategies like sequential exposure to diverse antigens or using adjuvants that promote naive responses are being explored to overcome imprinting. | |
| Microbiome Influence | The gut–lung axis influences mucosal immunity. Butyrate and aromatic amino acids promote mucosal IgA stability and MAIT/Tfh support. A rich microbiome provides continual stimuli (via microbial products) that keep mucosal immune cells primed and responsive. Dysbiosis (low diversity, loss of key species) can impair mucosal immune readiness, leading to weaker IgA responses and altered inflammation. | Gut microbes influence systemic T-cell differentiation and memory formation. Lower gut microbiome diversity has been associated with weaker systemic antibody and T-cell responses to SARS-CoV-2 vaccines and infections. Certain microbial products (e.g., LPS, peptidoglycans) translocating into circulation (especially during severe infections or with leaky gut) can exacerbate systemic inflammation. | |
| Age-related Variation | Older populations show reduced mucosal B and T-cell numbers (especially CD8⁺ T cells), diminished IgA class switching, and less efficient containment in the upper respiratory tract. Children rapidly produce IgA and IFNs, leading to more efficient virus containment in the upper respiratory tract. | Aged individuals show delayed systemic Tfh activation and weaker germinal center output; pediatric memory is more adaptable to variants but less durable. Immune senescence in older patients leads to fewer naive T cells and a bias toward memory cells that might not match new variants. In children, the systemic inflammatory response to coronaviruses is usually tempered (e.g. pediatric COVID-19 cases have lower circulating IL-6/IL-1β compared to adults, indicating less propensity for cytokine storm). Aged individuals often have weaker CD8⁺ T-cell responses and lower induction of interferons systemically, contributing to higher viral loads. Older individuals (>60 years old) show lower peak IgG levels, and shorter duration of protection. | |
| Sex-related Variation | Females exhibit stronger antiviral CD8+ T-cell responses, including more memory cells, leading to better viral control at mucosal sites. Sex differences in mucosal antibodies (IgA) are less consistent; however, some pediatric studies report higher mucosal antibody levels in females. | Males experience greater disease severity, partly due to delayed interferon responses and elevated inflammatory cytokines compared to females. Females generally produce higher systemic IgG titers, particularly against SARS-CoV-2 spike protein, compared to males. Females consistently achieve higher vaccine-induced antibody titers than males as well, with greater antibody persistence and neutralization capability. Additional vaccine booster doses, particularly with variant-specific vaccines, can mitigate the sex differences in immunity, bringing males to comparable antibody titers and protection levels as females. | |
| Infection vs. Vaccination | Infection or hybrid immunity induces broader mucosal immunity: abundant nasal and salivary IgA, higher levels of salivary IgG, lung-resident T cells, and long-lived plasma cells in the mucosa. Infection also targets multiple viral proteins, generating mucosal immunity to not just spike but other antigens. Mucosal vaccines enhance mucosal immunity and immune memory better than intramuscular vaccines. They mimic natural infection by inducing local IgA production and TRM formation. | Infection-derived Tfh cells promote more diverse systemic immunity. Vaccine responses depend on platform and adjuvant; live attenuated or protein-adjuvant vaccines might induce some mucosal IgA, whereas non-replicating platforms (mRNA, viral vectors) induce little mucosal response but strong systemic IgG. Adjuvants can skew responses (e.g., toward Th1 vs Th2). |