RESUMEN
In the periphery, Foxp3 expression is considered sufficient to maintain natural regulatory CD4(+) T-cell suppressive function. In this study, we challenge this model. Indeed, in mouse chimeras in which major histocompatibility complex (MHC) class II expression is restricted to the thymus, peripheral regulatory CD4(+) T cells lack suppressive activity. In addition, regulatory CD4(+) T cells recovered 5 days after transfer into recipient mice lacking expression of MHC class II molecules (self-deprived) are unable to inhibit the proliferative response of conventional CD4(+) T cells both in vitro and in vivo. Disruption of TCR/MHC class II interactions rapidly leads to alterations in the regulatory CD4(+) T-cell phenotype, the ability to respond to stimulation and to produce interleukin-10, and the transcriptional signature. Interestingly, self-deprivation does not affect Foxp3 expression indicating that in regulatory CD4(+) T cells, self-recognition induces unique transcriptional and functional features that do not rely on Foxp3 expression.
Asunto(s)
Factores de Transcripción Forkhead/fisiología , Tolerancia Inmunológica , Linfocitos T Reguladores/inmunología , Animales , Células Cultivadas , Quimera/inmunología , Técnicas de Cocultivo , Antígenos de Histocompatibilidad Clase II/fisiología , Interleucina-10/biosíntesis , Interleucina-10/fisiología , Activación de Linfocitos/inmunología , Ratones , Receptores de Antígenos de Linfocitos T/fisiología , Transcriptoma/inmunologíaRESUMEN
Lymphopenia is thought to be a major cause of tolerance breakdown. In a lymphopenic environment, self-recognition events induce some T cells to expand strongly (a mechanism known as spontaneous proliferation). In this study, we show that in C57BL/6 mice, the repertoire resulting from lymphopenia-induced spontaneous CD4(+) T-cell proliferation included a proportion of regulatory T cells as large as that observed in a normal mouse, and no autoimmune disorder was observed. By contrast, in nonobese diabetic mice, differences in the ability of conventional and regulatory T cells to expand in response to lymphopenia led to an unbalance between these 2 T-cell compartments at the expense of regulatory T cells, resulting in the onset of autoimmune diseases. Notably, this accounted for the rapid transfer of diabetes with small numbers of BDC2.5 CD4(+) T cells. Thus, lymphopenia does not itself induce autoimmunity, but it should be considered as a cofactor for the development of autoimmune disorders.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Linfocitos T/citología , Animales , Complejo CD3/biosíntesis , Linfocitos T CD4-Positivos/citología , Diferenciación Celular , Proliferación Celular , Citometría de Flujo/métodos , Antígenos Comunes de Leucocito/biosíntesis , Ligandos , Linfopenia/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Linfocitos T/inmunologíaRESUMEN
In vivo studies have shown that regulatory CD4(+) T cells regulate conventional CD4(+) T cell responses to self- and environmental Ags. However, it remains unclear whether regulatory CD4(+) T cells control CD8(+) T cell responses to self, directly, or indirectly by decreasing available CD4(+) T cell help. We have developed an experimental mouse model in which suppressive and helper T cells cannot mediate their functions. The mouse chimeras generated were not viable and rapidly developed multiple organ autoimmunity. These features were correlated with strong CD8(+) T cell activation and accumulation in both lymphoid and nonlymphoid organs. In vivo Ab treatment and secondary transfer experiments demonstrated that regulatory CD4(+) T cells play an important direct role in the prevention of peripheral CD8(+) T cell-mediated autoimmunity.
Asunto(s)
Autoinmunidad/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Autotolerancia/inmunología , Linfocitos T Reguladores/inmunología , Animales , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Factores de Transcripción Forkhead/análisis , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Mutantes , Linfocitos T Reguladores/metabolismoRESUMEN
Dendritic cell (DC) maturation state is a key parameter for the issue of DC-T cell cognate interaction, which determines the outcome of T cell activation. Indeed, immature DCs induce tolerance while fully mature DCs generate immunity. Here we show that, in the absence of any deliberate activation signal, DCs freshly isolated from mouse spleen spontaneously produce IL-12 and tumor necrosis factor-alpha and up-regulate co-stimulation molecules, even when directly re-injected into their natural environment. Furthermore, after their isolation, these cells acquire the capacity to induce specific T(h)1 responses in vivo. These results demonstrate that the sole isolation of spleen DCs leads to the full maturation of these cells, which therefore cannot be considered as immature DCs. Moreover, we also show that the kinetics of DC activation do not influence the polarization of T(h) response in vivo challenging the idea that exhausted DCs induce preferentially T(h)2 response. Altogether, these observations should be taken into account in all experiments based on the transfer of ex vivo purified DCs.