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A large body of evidence generated in the last two and a half years addresses the roles of T cells in SARS-CoV-2 infection and following vaccination. Infection or vaccination induces multi-epitope CD4 and CD8 T cell responses with polyfunctionality. Early T cell responses have been associated with mild COVID-19 outcomes. In concert with animal model data, these results suggest that while antibody responses are key to prevent infection, T cell responses may also play valuable roles in reducing disease severity and controlling infection. T cell memory after vaccination is sustained for at least six months. While neutralizing antibody responses are impacted by SARS-CoV-2 variants, most CD4 and CD8 T cell responses are preserved. This review highlights the extensive progress made, and the data and knowledge gaps that remain, in our understanding of T cell responses to SARS-CoV-2 and COVID-19 vaccines.
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COVID-19 , SARS-CoV-2 , Animales , Humanos , Vacunas contra la COVID-19 , Linfocitos T CD8-positivos , Anticuerpos AntiviralesRESUMEN
Throughout the body, T cells monitor MHC-bound ligands expressed on the surface of essentially all cell types. MHC ligands that trigger a T cell immune response are referred to as T cell epitopes. Identifying such epitopes enables tracking, phenotyping, and stimulating T cells involved in immune responses in infectious disease, allergy, autoimmunity, transplantation, and cancer. The specific T cell epitopes recognized in an individual are determined by genetic factors such as the MHC molecules the individual expresses, in parallel to the individual's environmental exposure history. The complexity and importance of T cell epitope mapping have motivated the development of computational approaches that predict what T cell epitopes are likely to be recognized in a given individual or in a broader population. Such predictions guide experimental epitope mapping studies and enable computational analysis of the immunogenic potential of a given protein sequence region.
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Epítopos de Linfocito T/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Animales , Biomarcadores , Biología Computacional/métodos , Susceptibilidad a Enfermedades , Antígenos de Histocompatibilidad/inmunología , Humanos , Ligandos , Aprendizaje Automático , Unión ProteicaRESUMEN
The dynamics of immunity to infection in infants remain obscure. Here, we used a multi-omics approach to perform a longitudinal analysis of immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in infants and young children by analyzing blood samples and weekly nasal swabs collected before, during, and after infection with Omicron and non-Omicron variants. Infection stimulated robust antibody titers that, unlike in adults, showed no sign of decay for up to 300 days. Infants mounted a robust mucosal immune response characterized by inflammatory cytokines, interferon (IFN) α, and T helper (Th) 17 and neutrophil markers (interleukin [IL]-17, IL-8, and CXCL1). The immune response in blood was characterized by upregulation of activation markers on innate cells, no inflammatory cytokines, but several chemokines and IFNα. The latter correlated with viral load and expression of interferon-stimulated genes (ISGs) in myeloid cells measured by single-cell multi-omics. Together, these data provide a snapshot of immunity to infection during the initial weeks and months of life.
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COVID-19 , SARS-CoV-2 , Adulto , Niño , Lactante , Humanos , Preescolar , SARS-CoV-2/metabolismo , Multiómica , Citocinas/metabolismo , Interferón-alfa , Inmunidad MucosaRESUMEN
Multiple COVID-19 vaccines, representing diverse vaccine platforms, successfully protect against symptomatic COVID-19 cases and deaths. Head-to-head comparisons of T cell, B cell, and antibody responses to diverse vaccines in humans are likely to be informative for understanding protective immunity against COVID-19, with particular interest in immune memory. Here, SARS-CoV-2-spike-specific immune responses to Moderna mRNA-1273, Pfizer/BioNTech BNT162b2, Janssen Ad26.COV2.S, and Novavax NVX-CoV2373 were examined longitudinally for 6 months 100% of individuals made memory CD4+ T cells, with cTfh and CD4-CTL highly represented after mRNA or NVX-CoV2373 vaccination. mRNA vaccines and Ad26.COV2.S induced comparable CD8+ T cell frequencies, though only detectable in 60-67% of subjects at 6 months. A differentiating feature of Ad26.COV2.S immunization was a high frequency of CXCR3+ memory B cells. mRNA vaccinees had substantial declines in antibodies, while memory T and B cells were comparatively stable. These results may also be relevant for insights against other pathogens.
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Vacunas contra la COVID-19 , COVID-19 , Ad26COVS1 , Anticuerpos Antivirales , Vacuna BNT162 , COVID-19/prevención & control , Humanos , Inmunidad Humoral , Memoria Inmunológica , SARS-CoV-2RESUMEN
We address whether T cell responses induced by different vaccine platforms (mRNA-1273, BNT162b2, Ad26.COV2.S, and NVX-CoV2373) cross-recognize early SARS-CoV-2 variants. T cell responses to early variants were preserved across vaccine platforms. By contrast, significant overall decreases were observed for memory B cells and neutralizing antibodies. In subjects â¼6 months post-vaccination, 90% (CD4+) and 87% (CD8+) of memory T cell responses were preserved against variants on average by AIM assay, and 84% (CD4+) and 85% (CD8+) preserved against Omicron. Omicron RBD memory B cell recognition was substantially reduced to 42% compared with other variants. T cell epitope repertoire analysis revealed a median of 11 and 10 spike epitopes recognized by CD4+ and CD8+ T cells, with average preservation > 80% for Omicron. Functional preservation of the majority of T cell responses may play an important role as a second-level defense against diverse variants.
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Vacunas contra la COVID-19/inmunología , Células B de Memoria/inmunología , Células T de Memoria/inmunología , SARS-CoV-2/inmunología , Ad26COVS1/administración & dosificación , Ad26COVS1/inmunología , Vacuna BNT162/administración & dosificación , Vacuna BNT162/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , COVID-19/patología , COVID-19/prevención & control , COVID-19/virología , Vacunas contra la COVID-19/administración & dosificación , Epítopos/inmunología , Epítopos de Linfocito T/inmunología , Humanos , Células B de Memoria/metabolismo , Células T de Memoria/metabolismo , SARS-CoV-2/aislamiento & purificación , SARS-CoV-2/metabolismo , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/inmunología , VacunaciónRESUMEN
Vaccine-mediated immunity often relies on the generation of protective antibodies and memory B cells, which commonly stem from germinal center (GC) reactions. An in-depth comparison of the GC responses elicited by SARS-CoV-2 mRNA vaccines in healthy and immunocompromised individuals has not yet been performed due to the challenge of directly probing human lymph nodes. Herein, through a fine-needle aspiration-based approach, we profiled the immune responses to SARS-CoV-2 mRNA vaccines in lymph nodes of healthy individuals and kidney transplant recipients (KTXs). We found that, unlike healthy subjects, KTXs presented deeply blunted SARS-CoV-2-specific GC B cell responses coupled with severely hindered T follicular helper cell, SARS-CoV-2 receptor binding domain-specific memory B cell, and neutralizing antibody responses. KTXs also displayed reduced SARS-CoV-2-specific CD4 and CD8 T cell frequencies. Broadly, these data indicate impaired GC-derived immunity in immunocompromised individuals and suggest a GC origin for certain humoral and memory B cell responses following mRNA vaccination.
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The adaptive immune system is important for control of most viral infections. The three fundamental components of the adaptive immune system are B cells (the source of antibodies), CD4+ T cells, and CD8+ T cells. The armamentarium of B cells, CD4+ T cells, and CD8+ T cells has differing roles in different viral infections and in vaccines, and thus it is critical to directly study adaptive immunity to SARS-CoV-2 to understand COVID-19. Knowledge is now available on relationships between antigen-specific immune responses and SARS-CoV-2 infection. Although more studies are needed, a picture has begun to emerge that reveals that CD4+ T cells, CD8+ T cells, and neutralizing antibodies all contribute to control of SARS-CoV-2 in both non-hospitalized and hospitalized cases of COVID-19. The specific functions and kinetics of these adaptive immune responses are discussed, as well as their interplay with innate immunity and implications for COVID-19 vaccines and immune memory against re-infection.
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Inmunidad Adaptativa , COVID-19/inmunología , SARS-CoV-2/fisiología , Factores de Edad , Linfocitos B/inmunología , COVID-19/complicaciones , COVID-19/epidemiología , COVID-19/patología , COVID-19/virología , Vacunas contra la COVID-19/inmunología , Ensayos Clínicos como Asunto , Humanos , Memoria Inmunológica , Factores Raciales , SARS-CoV-2/clasificación , Factores Sexuales , Subgrupos de Linfocitos T/inmunología , Carga Viral , Síndrome Post Agudo de COVID-19RESUMEN
T cell-mediated immunity plays an important role in controlling SARS-CoV-2 infection, but the repertoire of naturally processed and presented viral epitopes on class I human leukocyte antigen (HLA-I) remains uncharacterized. Here, we report the first HLA-I immunopeptidome of SARS-CoV-2 in two cell lines at different times post infection using mass spectrometry. We found HLA-I peptides derived not only from canonical open reading frames (ORFs) but also from internal out-of-frame ORFs in spike and nucleocapsid not captured by current vaccines. Some peptides from out-of-frame ORFs elicited T cell responses in a humanized mouse model and individuals with COVID-19 that exceeded responses to canonical peptides, including some of the strongest epitopes reported to date. Whole-proteome analysis of infected cells revealed that early expressed viral proteins contribute more to HLA-I presentation and immunogenicity. These biological insights, as well as the discovery of out-of-frame ORF epitopes, will facilitate selection of peptides for immune monitoring and vaccine development.
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Epítopos de Linfocito T/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Sistemas de Lectura Abierta/genética , Péptidos/inmunología , Proteoma/inmunología , SARS-CoV-2/inmunología , Células A549 , Alelos , Secuencia de Aminoácidos , Animales , Presentación de Antígeno/inmunología , COVID-19/inmunología , COVID-19/virología , Femenino , Células HEK293 , Humanos , Cinética , Masculino , Ratones , Péptidos/química , Linfocitos T/inmunologíaRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of vaccinated individuals is increasingly common but rarely results in severe disease, likely due to the enhanced potency and accelerated kinetics of memory immune responses. However, there have been few opportunities to rigorously study early recall responses during human viral infection. To better understand human immune memory and identify potential mediators of lasting vaccine efficacy, we used high-dimensional flow cytometry and SARS-CoV-2 antigen probes to examine immune responses in longitudinal samples from vaccinated individuals infected during the Omicron wave. These studies revealed heightened spike-specific responses during infection of vaccinated compared to unvaccinated individuals. Spike-specific cluster of differentiation (CD)4 T cells and plasmablasts expanded and CD8 T cells were robustly activated during the first week. In contrast, memory B cell activation, neutralizing antibody production and primary responses to nonspike antigens occurred during the second week. Collectively, these data demonstrate the functionality of vaccine-primed immune memory and highlight memory T cells as rapid responders during SARS-CoV-2 infection.
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The contribution of CD4+ T cells to protective or pathogenic immune responses to SARS-CoV-2 infection remains unknown. Here, we present single-cell transcriptomic analysis of >100,000 viral antigen-reactive CD4+ T cells from 40 COVID-19 patients. In hospitalized patients compared to non-hospitalized patients, we found increased proportions of cytotoxic follicular helper cells and cytotoxic T helper (TH) cells (CD4-CTLs) responding to SARS-CoV-2 and reduced proportion of SARS-CoV-2-reactive regulatory T cells (TREG). Importantly, in hospitalized COVID-19 patients, a strong cytotoxic TFH response was observed early in the illness, which correlated negatively with antibody levels to SARS-CoV-2 spike protein. Polyfunctional TH1 and TH17 cell subsets were underrepresented in the repertoire of SARS-CoV-2-reactive CD4+ T cells compared to influenza-reactive CD4+ T cells. Together, our analyses provide insights into the gene expression patterns of SARS-CoV-2-reactive CD4+ T cells in distinct disease severities.
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COVID-19/inmunología , SARS-CoV-2/genética , Células T Auxiliares Foliculares/inmunología , Linfocitos T Citotóxicos/inmunología , Linfocitos T Reguladores/inmunología , Transcriptoma , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Recuento de Linfocito CD4 , COVID-19/epidemiología , COVID-19/virología , Estudios de Cohortes , Inglaterra/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Índice de Severidad de la Enfermedad , Análisis de la Célula Individual/métodos , Glicoproteína de la Espiga del Coronavirus/inmunologíaRESUMEN
Understanding adaptive immunity to SARS-CoV-2 is important for vaccine development, interpreting coronavirus disease 2019 (COVID-19) pathogenesis, and calibration of pandemic control measures. Using HLA class I and II predicted peptide "megapools," circulating SARS-CoV-2-specific CD8+ and CD4+ T cells were identified in â¼70% and 100% of COVID-19 convalescent patients, respectively. CD4+ T cell responses to spike, the main target of most vaccine efforts, were robust and correlated with the magnitude of the anti-SARS-CoV-2 IgG and IgA titers. The M, spike, and N proteins each accounted for 11%-27% of the total CD4+ response, with additional responses commonly targeting nsp3, nsp4, ORF3a, and ORF8, among others. For CD8+ T cells, spike and M were recognized, with at least eight SARS-CoV-2 ORFs targeted. Importantly, we detected SARS-CoV-2-reactive CD4+ T cells in â¼40%-60% of unexposed individuals, suggesting cross-reactive T cell recognition between circulating "common cold" coronaviruses and SARS-CoV-2.
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Betacoronavirus/fisiología , Infecciones por Coronavirus/inmunología , Epítopos de Linfocito T , Neumonía Viral/inmunología , Betacoronavirus/genética , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , COVID-19 , Vacunas contra la COVID-19 , Convalecencia , Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/metabolismo , Infecciones por Coronavirus/prevención & control , Infecciones por Coronavirus/virología , Reacciones Cruzadas , Humanos , Leucocitos Mononucleares/inmunología , Pandemias , Neumonía Viral/sangre , Neumonía Viral/metabolismo , Neumonía Viral/virología , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus/metabolismo , Proteínas Virales/metabolismo , Vacunas Virales/inmunologíaRESUMEN
Limited knowledge is available on the relationship between antigen-specific immune responses and COVID-19 disease severity. We completed a combined examination of all three branches of adaptive immunity at the level of SARS-CoV-2-specific CD4+ and CD8+ T cell and neutralizing antibody responses in acute and convalescent subjects. SARS-CoV-2-specific CD4+ and CD8+ T cells were each associated with milder disease. Coordinated SARS-CoV-2-specific adaptive immune responses were associated with milder disease, suggesting roles for both CD4+ and CD8+ T cells in protective immunity in COVID-19. Notably, coordination of SARS-CoV-2 antigen-specific responses was disrupted in individuals ≥ 65 years old. Scarcity of naive T cells was also associated with aging and poor disease outcomes. A parsimonious explanation is that coordinated CD4+ T cell, CD8+ T cell, and antibody responses are protective, but uncoordinated responses frequently fail to control disease, with a connection between aging and impaired adaptive immune responses to SARS-CoV-2.
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Inmunidad Adaptativa , Antígenos Virales/inmunología , Infecciones por Coronavirus/patología , Neumonía Viral/patología , Enfermedad Aguda , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Betacoronavirus/inmunología , Betacoronavirus/aislamiento & purificación , Betacoronavirus/metabolismo , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , COVID-19 , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/virología , Citocinas/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/inmunología , Neumonía Viral/virología , SARS-CoV-2 , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
Many approaches to identify therapeutically relevant neoantigens couple tumor sequencing with bioinformatic algorithms and inferred rules of tumor epitope immunogenicity. However, there are no reference data to compare these approaches, and the parameters governing tumor epitope immunogenicity remain unclear. Here, we assembled a global consortium wherein each participant predicted immunogenic epitopes from shared tumor sequencing data. 608 epitopes were subsequently assessed for T cell binding in patient-matched samples. By integrating peptide features associated with presentation and recognition, we developed a model of tumor epitope immunogenicity that filtered out 98% of non-immunogenic peptides with a precision above 0.70. Pipelines prioritizing model features had superior performance, and pipeline alterations leveraging them improved prediction performance. These findings were validated in an independent cohort of 310 epitopes prioritized from tumor sequencing data and assessed for T cell binding. This data resource enables identification of parameters underlying effective anti-tumor immunity and is available to the research community.
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Antígenos de Neoplasias/inmunología , Epítopos/inmunología , Neoplasias/inmunología , Alelos , Presentación de Antígeno/inmunología , Estudios de Cohortes , Humanos , Péptidos/inmunología , Receptor de Muerte Celular Programada 1 , Reproducibilidad de los ResultadosRESUMEN
Understanding immune responses to SARS-CoV-2 messenger RNA (mRNA) vaccines is of great interest, principally because of the poor knowledge about the mechanisms of protection. In the present study, we analyzed longitudinally B cell and T cell memory programs against the spike (S) protein derived from ancestral SARS-CoV-2 (Wuhan-1), B.1.351 (beta), B.1.617.2 (delta) and B.1.1.529 (omicron) variants of concern (VOCs) after immunization with an mRNA-based vaccine (Pfizer). According to the magnitude of humoral responses 3 months after the first dose, we identified high and low responders. Opposite to low responders, high responders were characterized by enhanced antibody-neutralizing activity, increased frequency of central memory T cells and durable S-specific CD8+ T cell responses. Reduced binding antibodies titers combined with long-term specific memory T cells that had distinct polyreactive properties were found associated with subsequent breakthrough with VOCs in low responders. These results have important implications for the design of new vaccines and new strategies for booster follow-up.
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COVID-19 , Vacunas Virales , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Linfocitos T CD8-positivos , COVID-19/prevención & control , Humanos , ARN Mensajero/genética , SARS-CoV-2 , VacunaciónRESUMEN
Ebola virus (EBOV) remains a public health threat. We performed a longitudinal study of B cell responses to EBOV in four survivors of the 2014 West African outbreak. Infection induced lasting EBOV-specific immunoglobulin G (IgG) antibodies, but their subclass composition changed over time, with IgG1 persisting, IgG3 rapidly declining, and IgG4 appearing late. Striking changes occurred in the immunoglobulin repertoire, with massive recruitment of naive B cells that subsequently underwent hypermutation. We characterized a large panel of EBOV glycoprotein-specific monoclonal antibodies (mAbs). Only a small subset of mAbs that bound glycoprotein by ELISA recognized cell-surface glycoprotein. However, this subset contained all neutralizing mAbs. Several mAbs protected against EBOV disease in animals, including one mAb that targeted an epitope under evolutionary selection during the 2014 outbreak. Convergent antibody evolution was seen across multiple donors, particularly among VH3-13 neutralizing antibodies specific for the GP1 core. Our study provides a benchmark for assessing EBOV vaccine-induced immunity.
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Anticuerpos Monoclonales/inmunología , Linfocitos B/fisiología , Fiebre Hemorrágica Ebola/inmunología , Adulto , Secuencia de Aminoácidos/genética , Animales , Anticuerpos Monoclonales/aislamiento & purificación , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Linfocitos B/metabolismo , Chlorocebus aethiops , Vacunas contra el Virus del Ébola/inmunología , Ebolavirus/genética , Ebolavirus/metabolismo , Ebolavirus/patogenicidad , Epítopos/sangre , Femenino , Glicoproteínas/genética , Fiebre Hemorrágica Ebola/metabolismo , Fiebre Hemorrágica Ebola/virología , Humanos , Inmunoglobulina G/inmunología , Células Jurkat , Estudios Longitudinales , Masculino , Ratones , Ratones Endogámicos BALB C , Sobrevivientes , Células Vero , Proteínas del Envoltorio Viral/genéticaRESUMEN
Herpes zoster (shingles) causes significant morbidity in immune compromised hosts and older adults. Whereas a vaccine is available for prevention of shingles, its efficacy declines with age. To help to understand the mechanisms driving vaccinal responses, we constructed a multiscale, multifactorial response network (MMRN) of immunity in healthy young and older adults immunized with the live attenuated shingles vaccine Zostavax. Vaccination induces robust antigen-specific antibody, plasmablasts, and CD4+ T cells yet limited CD8+ T cell and antiviral responses. The MMRN reveals striking associations between orthogonal datasets, such as transcriptomic and metabolomics signatures, cell populations, and cytokine levels, and identifies immune and metabolic correlates of vaccine immunity. Networks associated with inositol phosphate, glycerophospholipids, and sterol metabolism are tightly coupled with immunity. Critically, the sterol regulatory binding protein 1 and its targets are key integrators of antibody and T follicular cell responses. Our approach is broadly applicable to study human immunity and can help to identify predictors of efficacy as well as mechanisms controlling immunity to vaccination.
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Vacuna contra el Herpes Zóster/inmunología , Inmunidad Adaptativa , Adulto , Anciano , Envejecimiento , Formación de Anticuerpos , Linfocitos T CD4-Positivos/inmunología , Femenino , Citometría de Flujo , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Fosfatos de Inositol/inmunología , Estudios Longitudinales , Masculino , Metabolómica , Persona de Mediana Edad , Caracteres Sexuales , Esteroles/metabolismo , Carga ViralRESUMEN
The brutal toll of another viral pandemic can be blunted by investing now in research that uncovers mechanisms of broad-based immunity so we may have vaccines and therapeutics at the ready. We do not know exactly what pathogen may trigger the next wave or next pandemic. We do know, however, that the human immune system must respond and must be bolstered with effective vaccines and other therapeutics to preserve lives and livelihoods. These countermeasures must focus on features conserved among families of pathogens in order to be responsive against something yet to emerge. Here, we focus on immunological approaches to mitigate the impact of the next emerging virus pandemic by developing vaccines that elicit both broadly protective antibodies and T cells. Identifying human immune mechanisms of broad protection against virus families with pandemic potential will be our best defense for humanity in the future.
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COVID-19 , Vacunas , Anticuerpos Antivirales , Humanos , Pandemias/prevención & control , SARS-CoV-2 , Linfocitos TRESUMEN
Many immunocompromised patients mount suboptimal humoral immunity after SARS-CoV-2 mRNA vaccination. Here, we assessed the single-cell profile of SARS-CoV-2-specific T cells post-mRNA vaccination in healthy individuals and patients with various forms of immunodeficiencies. Impaired vaccine-induced cell-mediated immunity was observed in many immunocompromised patients, particularly in solid-organ transplant and chronic lymphocytic leukemia patients. Notably, individuals with an inherited lack of mature B cells, i.e., X-linked agammaglobulinemia (XLA) displayed highly functional spike-specific T cell responses. Single-cell RNA-sequencing further revealed that mRNA vaccination induced a broad functional spectrum of spike-specific CD4+ and CD8+ T cells in healthy individuals and patients with XLA. These responses were founded on polyclonal repertoires of CD4+ T cells and robust expansions of oligoclonal effector-memory CD45RA+ CD8+ T cells with stem-like characteristics. Collectively, our data provide the functional continuum of SARS-CoV-2-specific T cell responses post-mRNA vaccination, highlighting that cell-mediated immunity is of variable functional quality across immunodeficiency syndromes.
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COVID-19 , SARS-CoV-2 , Anticuerpos Antivirales , Linfocitos T CD8-positivos , COVID-19/prevención & control , Humanos , Inmunidad Humoral , ARN Mensajero/genética , Síndrome , Vacunación , Proteínas del Envoltorio ViralRESUMEN
Human inborn errors of IFN-γ immunity underlie mycobacterial diseases. We describe patients with Mycobacterium bovis (BCG) disease who are homozygous for loss-of-function mutations of SPPL2A. This gene encodes a transmembrane protease that degrades the N-terminal fragment (NTF) of CD74 (HLA invariant chain) in antigen-presenting cells. The CD74 NTF therefore accumulates in the HLA class II+ myeloid and lymphoid cells of SPPL2a-deficient patients. This toxic fragment selectively depletes IL-12- and IL-23-producing CD1c+ conventional dendritic cells (cDC2s) and their circulating progenitors. Moreover, SPPL2a-deficient memory TH1* cells selectively fail to produce IFN-γ when stimulated with mycobacterial antigens in vitro. Finally, Sppl2a-/- mice lack cDC2s, have CD4+ T cells that produce small amounts of IFN-γ after BCG infection, and are highly susceptible to infection with BCG or Mycobacterium tuberculosis. These findings suggest that inherited SPPL2a deficiency in humans underlies mycobacterial disease by decreasing the numbers of cDC2s and impairing IFN-γ production by mycobacterium-specific memory TH1* cells.