RESUMEN
Foxp3-expressing CD4+ regulatory T (Treg) cells play key roles in the prevention of autoimmunity and the maintenance of immune homeostasis and represent a major barrier to the induction of robust antitumor immune responses. Thus, a clear understanding of the mechanisms coordinating Treg cell differentiation is crucial for understanding numerous facets of health and disease and for developing approaches to modulate Treg cells for clinical benefit. Here, we discuss current knowledge of the signals that coordinate Treg cell development, the antigen-presenting cell types that direct Treg cell selection, and the nature of endogenous Treg cell ligands, focusing on evidence from studies in mice. We also highlight recent advances in this area and identify key unanswered questions.
Asunto(s)
Diferenciación Celular/inmunología , Linfopoyesis/inmunología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Animales , Presentación de Antígeno/inmunología , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/metabolismo , Biomarcadores , Diferenciación Celular/genética , Supresión Clonal , Selección Clonal Mediada por Antígenos , Humanos , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Linfopoyesis/genética , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Reguladores/citología , Timo/citología , Timo/inmunología , Timo/metabolismoRESUMEN
Recent progress in both conceptual and technological approaches to human immunology have rejuvenated a field that has long been in the shadow of the inbred mouse model. This is a healthy development both for the clinical relevance of immunology and for the fact that it is a way to gain access to the wealth of phenomenology in the many human diseases that involve the immune system. This is where we are likely to discover new immunological mechanisms and principals, especially those involving genetic heterogeneity or environmental influences that are difficult to model effectively in inbred mice. We also suggest that there are likely to be novel immunological mechanisms in long-lived, less fecund mammals such as human beings since they must remain healthy far longer than short-lived rodents in order for the species to survive.
Asunto(s)
Sistema Inmunológico/fisiología , Inmunidad , Animales , Linfocitos B/inmunología , Linfocitos B/metabolismo , Evolución Biológica , Variación Biológica Poblacional , Supresión Clonal/inmunología , Interacciones Huésped-Patógeno/inmunología , Humanos , Memoria Inmunológica , Modelos Animales , Receptores de Antígenos de Linfocitos T/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
Thymocytes bearing autoreactive T cell receptors (TCRs) are agonist-signaled by TCR/co-stimulatory molecules to either undergo clonal deletion or to differentiate into specialized regulatory T (Treg) or effector T (Teff) CD4+ cells. How these different fates are achieved during development remains poorly understood. We now document that deletion and differentiation are agonist-signaled at different times during thymic selection and that Treg and Teff cells both arise after clonal deletion as alternative lineage fates of agonist-signaled CD4+CD25+ precursors. Disruption of agonist signaling induces CD4+CD25+ precursors to initiate Foxp3 expression and become Treg cells, whereas persistent agonist signaling induces CD4+CD25+ precursors to become IL-2+ Teff cells. Notably, we discovered that transforming growth factor-ß induces Foxp3 expression and promotes Treg cell development by disrupting weaker agonist signals and that Foxp3 expression is not induced by IL-2 except under non-physiological in vivo conditions. Thus, TCR signaling disruption versus persistence is a general mechanism of lineage fate determination in the thymus that directs development of agonist-signaled autoreactive thymocytes.
Asunto(s)
Supresión Clonal , Timocitos , Timocitos/metabolismo , Interleucina-2/genética , Interleucina-2/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Timo/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Linfocitos T Reguladores/metabolismoRESUMEN
The thymus contains a diversity of dendritic cells (DCs) that exist in defined locations and have different antigen-processing and -presenting features. This suggests that they play nonredundant roles in mediating thymocyte selection. In an effort to eliminate SIRPα+ classic DC2 subsets, we discovered that a substantial proportion expresses the surface lectin, CD301b, in the thymus. These cells resemble the CD301b+ type 2 immune response promoting DCs that are present in the skin-draining lymph nodes. Transcriptional and phenotypic comparison to other DC subsets in the thymus revealed that thymic CD301b+ cDCs represent an activated state that exhibits enhanced antigen processing and presentation. Furthermore, a CD301b+ cDC2 subset demonstrated a type 2 cytokine signature and required steady-state interleukin-4 receptor signaling. Selective ablation of CD301b+ cDC2 subsets impaired clonal deletion without affecting regulatory T cells (Treg cells). The T cell receptor α repertoire sequencing confirmed that a cDC2 subset promotes deletion of conventional T cells with minimal effect on Treg cell selection. Together, these findings suggest that cytokine-induced activation of DCs in the thymus substantially enforces central tolerance.
Asunto(s)
Supresión Clonal , Células Dendríticas , Presentación de Antígeno , Citocinas , Activación de Linfocitos , TimoRESUMEN
Follicular regulatory T (TFR) cells have specialized roles in modulating follicular helper T (TFH) cell activation of B cells. However, the precise role of TFR cells in controlling antibody responses to foreign antigens and autoantigens in vivo is still unclear due to a lack of specific tools. A TFR cell-deleter mouse was developed that selectively deletes TFR cells, facilitating temporal studies. TFR cells were found to regulate early, but not late, germinal center (GC) responses to control antigen-specific antibody and B cell memory. Deletion of TFR cells also resulted in increased self-reactive immunoglobulin (Ig) G and IgE. The increased IgE levels led us to interrogate the role of TFR cells in house dust mite models. TFR cells were found to control TFH13 cell-induced IgE. In vivo, loss of TFR cells increased house-dust-mite-specific IgE and lung inflammation. Thus, TFR cells control IgG and IgE responses to vaccines, allergens and autoantigens, and exert critical immunoregulatory functions before GC formation.
Asunto(s)
Linfocitos B/inmunología , Centro Germinal/inmunología , Hipersensibilidad/inmunología , Neumonía/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Reguladores/inmunología , Animales , Antígenos Dermatofagoides/inmunología , Autoantígenos/inmunología , Supresión Clonal/genética , Modelos Animales de Enfermedad , Humanos , Tolerancia Inmunológica , Inmunidad Humoral , Inmunoglobulina E/metabolismo , Inmunoglobulina G/metabolismo , Memoria Inmunológica , Interleucina-13/metabolismo , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Pyroglyphidae/inmunologíaRESUMEN
While inbred mice have informed most of what we know about the immune system in the modern era, they have clear limitations with respect to their ability to be informative regarding genetic heterogeneity or microbial influences. They have also not been very predictive as models of human disease or vaccination results. Although there are concerted attempts to compensate for these flaws, the rapid rise of human studies, driven by both technical and conceptual advances, promises to fill in these gaps, as well as provide direct information about human diseases and vaccination responses. Work on human immunity has already provided important additional perspectives on basic immunology such as the importance of clonal deletion to self-tolerance, and while many challenges remain, it seems inevitable that "the human model" will continue to inform us about the immune system and even allow for the discovery of new mechanisms.
Asunto(s)
Supresión Clonal , Sistema Inmunológico , Animales , Humanos , Sistema Inmunológico/fisiología , Ratones , Autotolerancia , VacunaciónRESUMEN
The T cell antigen receptor (TCR) expressed on thymocytes interacts with self-peptide major histocompatibility complex (pMHC) ligands to signal apoptosis or survival. Here, we found that negative-selection ligands induced thymocytes to exert forces on the TCR and the co-receptor CD8 and formed cooperative TCR-pMHC-CD8 trimolecular 'catch bonds', whereas positive-selection ligands induced less sustained thymocyte forces on TCR and CD8 and formed shorter-lived, independent TCR-pMHC and pMHC-CD8 bimolecular 'slip bonds'. Catch bonds were not intrinsic to either the TCR-pMHC or the pMHC-CD8 arm of the trans (cross-junctional) heterodimer but resulted from coupling of the extracellular pMHC-CD8 interaction to the intracellular interaction of CD8 with TCR-CD3 via associated kinases to form a cis (lateral) heterodimer capable of inside-out signaling. We suggest that the coupled trans-cis heterodimeric interactions form a mechanotransduction loop that reinforces negative-selection signaling that is distinct from positive-selection signaling in the thymus.
Asunto(s)
Mecanotransducción Celular/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Timocitos/inmunología , Timo/inmunología , Animales , Supresión Clonal/inmunología , Ratones , Ratones Transgénicos , Receptores de Antígenos de Linfocitos T/metabolismo , Timocitos/metabolismoRESUMEN
Studies of repertoires of mouse monoclonal CD4(+) T cells have revealed several mechanisms of self-tolerance; however, which mechanisms operate in normal repertoires is unclear. Here we studied polyclonal CD4(+) T cells specific for green fluorescent protein expressed in various organs, which allowed us to determine the effects of specific expression patterns on the same epitope-specific T cells. Peptides presented uniformly by thymic antigen-presenting cells were tolerated by clonal deletion, whereas peptides excluded from the thymus were ignored. Peptides with limited thymic expression induced partial clonal deletion and impaired effector T cell potential but enhanced regulatory T cell potential. These mechanisms were also active for T cell populations specific for endogenously expressed self antigens. Thus, the immunotolerance of polyclonal CD4(+) T cells was maintained by distinct mechanisms, according to self-peptide expression patterns.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Expresión Génica , Tolerancia Inmunológica , Péptidos/genética , Péptidos/inmunología , Secuencia de Aminoácidos , Animales , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/metabolismo , Autoantígenos/química , Autoantígenos/genética , Autoantígenos/inmunología , Autoinmunidad , Supresión Clonal/genética , Supresión Clonal/inmunología , Epítopos de Linfocito T/química , Epítopos de Linfocito T/genética , Epítopos de Linfocito T/inmunología , Femenino , Genes Reporteros , Ratones , Ratones Transgénicos , Péptidos/química , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Timo/inmunología , Timo/metabolismoRESUMEN
Combination immune checkpoint blockade targeting CTLA-4 and PD-1 is thought to reinvigorate exhausted T cells better than monotherapies. In this issue of Immunity, Pai et al. (2019) show that, in the setting of low tumor burden, this combination regimen promotes interferon-γ-dependent T cell hyperactivation and death and thus favors tumor progression.
Asunto(s)
Neoplasias , Linfocitos T , Antígeno CTLA-4 , Supervivencia Celular , Supresión Clonal , Resistencia a Antineoplásicos , Humanos , Inmunoterapia , Interferón gammaRESUMEN
Resistance to checkpoint-blockade treatments is a challenge in the clinic. We found that although treatment with combined anti-CTLA-4 and anti-PD-1 improved control of established tumors, this combination compromised anti-tumor immunity in the low tumor burden (LTB) state in pre-clinical models as well as in melanoma patients. Activated tumor-specific T cells expressed higher amounts of interferon-γ (IFN-γ) receptor and were more susceptible to apoptosis than naive T cells. Combination treatment induced deletion of tumor-specific T cells and altered the T cell repertoire landscape, skewing the distribution of T cells toward lower-frequency clonotypes. Additionally, combination therapy induced higher IFN-γ production in the LTB state than in the high tumor burden (HTB) state on a per-cell basis, reflecting a less exhausted immune status in the LTB state. Thus, elevated IFN-γ secretion in the LTB state contributes to the development of an immune-intrinsic mechanism of resistance to combination checkpoint blockade, highlighting the importance of achieving the optimal magnitude of immune stimulation for successful combination immunotherapy strategies.
Asunto(s)
Anticuerpos Monoclonales/farmacología , Antígeno CTLA-4/antagonistas & inhibidores , Resistencia a Antineoplásicos/efectos de los fármacos , Interferón gamma/farmacología , Neoplasias Experimentales/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Linfocitos T/efectos de los fármacos , Animales , Anticuerpos Monoclonales/inmunología , Antígeno CTLA-4/inmunología , Antígeno CTLA-4/metabolismo , Línea Celular Tumoral , Supresión Clonal/efectos de los fármacos , Supresión Clonal/inmunología , Resistencia a Antineoplásicos/inmunología , Humanos , Interferón gamma/inmunología , Interferón gamma/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Neoplasias Experimentales/inmunología , Neoplasias Experimentales/metabolismo , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Carga Tumoral/efectos de los fármacos , Carga Tumoral/inmunologíaRESUMEN
Self-reactivity was once seen as a potential characteristic of T cells that was eliminated by clonal selection to protect the host from autoimmune pathology. It is now understood that the T cell repertoire is in fact broadly self-reactive, even self-centered. The strength with which a T cell reacts to self ligands and the environmental context in which this reaction occurs influence almost every aspect of T cell biology, from development to differentiation to effector function. Here we highlight recent advances and discoveries that relate to T cell self-reactivity, with a particular emphasis on T cell antigen receptor (TCR) signaling thresholds.
Asunto(s)
Autoinmunidad/inmunología , Supresión Clonal/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Transducción de Señal/inmunología , Linfocitos T/inmunología , HumanosRESUMEN
The promiscuous expression of tissue-restricted antigens in the thymus, driven in part by autoimmune regulator (Aire), is critical for the protection of peripheral tissues from autoimmune attack. Aire-dependent processes are thought to promote both clonal deletion and the development of Foxp3(+) regulatory T (Treg) cells, suggesting that autoimmunity associated with Aire deficiency results from two failed tolerance mechanisms. Here, examination of autoimmune lesions in Aire(-/-) mice revealed an unexpected third possibility. We found that the predominant conventional T cell clonotypes infiltrating target lesions express antigen receptors that were preferentially expressed by Foxp3(+) Treg cells in Aire(+/+) mice. Thus, Aire enforces immune tolerance by ensuring that distinct autoreactive T cell specificities differentiate into the Treg cell lineage; dysregulation of this process results in the diversion of Treg cell-biased clonotypes into pathogenic conventional T cells.
Asunto(s)
Autoinmunidad , Tolerancia Inmunológica , Próstata/inmunología , Subgrupos de Linfocitos T/fisiología , Linfocitos T Reguladores/fisiología , Timo/inmunología , Factores de Transcripción/metabolismo , Animales , Autoantígenos/inmunología , Autoinmunidad/genética , Diferenciación Celular , Linaje de la Célula , Supresión Clonal , Selección Clonal Mediada por Antígenos , Células Clonales , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Tolerancia Inmunológica/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Especificidad del Receptor de Antígeno de Linfocitos T , Factores de Transcripción/genética , Proteína AIRERESUMEN
Clonal deletion of autoreactive thymocytes is important for self-tolerance, but the intrathymic signals that induce clonal deletion have not been clearly identified. We now report that clonal deletion during negative selection required CD28-mediated costimulation of autoreactive thymocytes at the CD4(+)CD8(lo) intermediate stage of differentiation. Autoreactive thymocytes were prevented from undergoing clonal deletion by either a lack of CD28 costimulation or transgenic overexpression of the antiapoptotic factors Bcl-2 or Mcl-1, with surviving thymocytes differentiating into anergic CD4(-)CD8(-) double-negative thymocytes positive for the T cell antigen receptor αß subtype (TCRαß) that 'preferentially' migrated to the intestine, where they re-expressed CD8α and were sequestered as CD8αα(+) intraepithelial lymphocytes (IELs). Our study identifies costimulation by CD28 as the intrathymic signal required for clonal deletion and identifies CD8αα(+) IELs as the developmental fate of autoreactive thymocytes that survive negative selection.
Asunto(s)
Diferenciación Celular/inmunología , Supresión Clonal/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Timocitos/inmunología , Timo/inmunología , Animales , Antígenos CD28/inmunología , Antígenos CD4/inmunología , Antígenos CD8/inmunología , Citometría de Flujo , Tolerancia Inmunológica/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Transducción de Señal/inmunología , Timocitos/citología , Timo/citologíaRESUMEN
It has been shown that self-reactive T cells can be detected in the periphery. In this issue of Immunity, Yu et al. (2015) show that clonal deletion prunes the T cell repertoire but does not eliminate self-reactive T cell clones.
Asunto(s)
Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Supresión Clonal , Animales , Femenino , Humanos , MasculinoRESUMEN
It has long been thought that clonal deletion efficiently removes almost all self-specific T cells from the peripheral repertoire. We found that self-peptide MHC-specific CD8(+) T cells in the blood of healthy humans were present in frequencies similar to those specific for non-self antigens. For the Y chromosome-encoded SMCY antigen, self-specific T cells exhibited only a 3-fold lower average frequency in males versus females and were anergic with respect to peptide activation, although this inhibition could be overcome by a stronger stimulus. We conclude that clonal deletion prunes but does not eliminate self-specific T cells and suggest that to do so would create holes in the repertoire that pathogens could readily exploit. In support of this hypothesis, we detected T cells specific for all 20 amino acid variants at the p5 position of a hepatitis C virus epitope in a random group of blood donors.
Asunto(s)
Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Supresión Clonal , Animales , Variación Antigénica , Femenino , Citometría de Flujo , Humanos , Masculino , Ratones , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Autotolerancia/inmunologíaRESUMEN
The origin and developmental pathway of intestinal T cell receptor αß(+) CD4(-)CD8ß(-) intraepithelial lymphocytes (unconventional iIELs), a major population of innate-like resident cytolytic T cells, have remained elusive. By cloning and expressing several TCRs isolated from unconventional iIELs, we identified immature CD4(lo)CD8(lo)(DP(lo))CD69(hi)PD-1(hi) thymocytes as the earliest postsignaling precursors for these cells. Although these precursors displayed multiple signs of elevated TCR signaling, a sizeable fraction of them escaped deletion to selectively engage in unconventional iIEL differentiation. Conversely, TCRs cloned from DP(lo)CD69(hi)PD-1(hi) thymocytes, a population enriched in autoreactive thymocytes, selectively gave rise to unconventional iIELs upon transgenic expression. Thus, the unconventional iIEL precursor overlaps with the DP(lo) population undergoing negative selection, indicating that, concomitant with the downregulation of both CD4 and CD8 coreceptors, a balance between apoptosis and survival signals results in outcomes as divergent as clonal deletion and differentiation to the unconventional iIEL lineage.
Asunto(s)
Linfocitos T CD4-Positivos/citología , Linfocitos T CD8-positivos/citología , Diferenciación Celular/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Animales , Antígenos CD/biosíntesis , Antígenos CD/genética , Antígenos CD/inmunología , Antígenos de Diferenciación de Linfocitos T/biosíntesis , Antígenos de Diferenciación de Linfocitos T/genética , Antígenos de Diferenciación de Linfocitos T/inmunología , Apoptosis/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Linaje de la Célula/inmunología , Células Cultivadas , Supresión Clonal/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Lectinas Tipo C/biosíntesis , Lectinas Tipo C/genética , Lectinas Tipo C/inmunología , Ratones , Ratones Transgénicos , Receptor de Muerte Celular Programada 1/biosíntesis , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/inmunología , Transducción de Señal/inmunologíaRESUMEN
Deficiency for AIRE/Aire in both humans and mice results in the development of organ-specific autoimmune disease. We tested whether augmented and/or dysregulated AIRE/Aire expression might be also prone to the breakdown of self-tolerance. To define the effect of augmented Aire expression on the development of autoimmunity, antigen-specific clonal deletion and production of clonotypic regulatory T cells (Tregs) in the thymus were examined using mice expressing two additional copies of Aire in a heterozygous state (3xAire-knockin mice: 3xAire-KI). We found that both clonal deletion of autoreactive T cells and production of clonotypic Tregs in the thymus from 3xAire-KI were impaired in a T-cell receptor-transgenic system. Furthermore, 3xAire-KI females showed higher scores of experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein than wild-type littermates, suggesting that augmented Aire expression exacerbates organ-specific autoimmunity under disease-prone conditions. In humans, we found that one patient with amyopathic dermatomyositis showed CD3- CD19- cells expressing AIRE in the peripheral blood before the treatment but not during the remission phase treated with immunosuppressive drugs. Thus, not only loss of function of AIRE/Aire but also augmented and/or dysregulated expression of AIRE/Aire should be considered for the pathogenesis of organ-specific autoimmunity. We suggest that further analyses should be pursued to establish a novel link between organ-specific autoimmune disease and dysregulated AIRE expression in clinical settings.
Asunto(s)
Autoinmunidad , Encefalomielitis Autoinmune Experimental , Animales , Supresión Clonal , Femenino , Humanos , Tolerancia Inmunológica , Ratones , Glicoproteína Mielina-Oligodendrócito , TimoRESUMEN
Thymically derived Foxp3⺠regulatory T (Treg) cells have a propensity to recognize self-peptide:MHC complexes, but their ability to respond to epitope-defined foreign antigens during infectious challenge has not been demonstrated. Here we show that pulmonary infection with Mycobacterium tuberculosis (Mtb), but not Listeria monocytogenes (Lm), induced robust lymph node expansion of a highly activated population of pathogen-specific Treg cells from the pre-existing pool of thymically derived Treg cells. These antigen-specific Treg cells peaked in numbers 3 weeks after infection but subsequently underwent selective elimination driven, in part, by interleukin-12-induced intrinsic expression of the Th1-cell-promoting transcription factor T-bet. Thus, the initial Mtb-induced inflammatory response promotes pathogen-specific Treg cell proliferation, but these cells are actively culled later, probably to prevent suppression during later stages of infection. These findings have important implications for the prevention and treatment of tuberculosis and other chronic diseases in which antigen-specific Treg cells restrict immunity.
Asunto(s)
Factores de Transcripción Forkhead/metabolismo , Interleucina-12/inmunología , Mycobacterium tuberculosis/inmunología , Proteínas de Dominio T Box/metabolismo , Linfocitos T Reguladores/inmunología , Células TH1/inmunología , Tuberculosis Pulmonar/inmunología , Animales , Antígenos Bacterianos/inmunología , Proteínas Bacterianas/inmunología , Proliferación Celular , Células Cultivadas , Supresión Clonal , Epítopos de Linfocito T/inmunología , Factores de Transcripción Forkhead/genética , Evasión Inmune , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fragmentos de Péptidos/inmunología , Proteínas de Dominio T Box/genética , Linfocitos T Reguladores/microbiología , Timo/patologíaRESUMEN
A layer of mucus functions to segregate contents of the intestinal lumen from the intestinal epithelium. The MUC2 mucin is the primary constituent of intestinal mucus and plays critical protective roles against luminal microbes and other noxious agents. In this study, we investigated whether MUC2 helps maintain CD8 T cell tolerance toward intestinal luminal Ags by gavaging wild-type and Muc2-/- mice with a model Ag and monitoring immune responses posttreatment. We report that orally delivered OVA rapidly disseminates through the blood of Muc2-/- (but not control) mice and causes immune activation of Ag-specific CD8 T cells at both local and distal sites. Further, the administration of oral OVA to Muc2-/- mice led to its presentation by thymic dendritic cells and the deletion of Ag-specific thymocytes. Collectively, our findings suggest that intestinal mucus helps limit the shaping of the TCR repertoire of developing thymocytes by intestinal luminal Ags.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Intestinos/fisiología , Mucina 2/metabolismo , Moco/metabolismo , Administración Oral , Animales , Antígenos/inmunología , Diferenciación Celular , Proliferación Celular , Supresión Clonal , Tolerancia Inmunológica , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mucina 2/genéticaRESUMEN
Deletion or Treg cell differentiation are alternative fates of autoreactive MHCII-restricted thymocytes. How these different modes of tolerance determine the size and composition of polyclonal cohorts of autoreactive T cells with shared specificity is poorly understood. We addressed how tolerance to a naturally expressed autoantigen of the central nervous system shapes the CD4 T cell repertoire. Specific cells in the tolerant peripheral repertoire either were Foxp3+ or displayed anergy hallmarks and, surprisingly, were at least as frequent as in the nontolerant repertoire. Despite this apparent lack of deletional tolerance, repertoire inventories uncovered that some T cell receptors (TCRs) were lost from the CD4 T cell pool, whereas others mediated Treg cell differentiation. The antigen responsiveness of these TCRs supported an affinity model of central tolerance. Importantly, the contribution of different diverter TCRs to the nascent thymic Treg cell population reflected their antigen reactivity rather than their frequency among precursors. This reveals a multilayered TCR hierarchy in CD4 T cell tolerance that separates deleted and diverted TCRs and assures that the Treg cell compartment is filled with cells of maximal permissive antigen reactivity.