RESUMO
Memory-phenotype CD8(+) T cells can arise even in the absence of overt Ag stimulation. Virtual memory (VM) CD8(+) T cells are CD8(+) T cells that develop a memory phenotype in the periphery of wild-type mice in an IL-15-dependent manner. Innate CD8(+) T cells, in contrast, are memory-phenotype CD8(+) T cells that develop in the thymus in response to elevated thymic IL-4. It is not clear whether VM cells and innate CD8(+) T cells represent two independent T cell lineages or whether they arise through similar processes. In this study, we use mice deficient in Nedd4-family interacting protein 1 to show that overproduction of IL-4 in the periphery leads to an expanded VM population. Nedd4-family interacting protein 1(-/-) CD4(+) T cells produce large amounts of IL-4 due to a defect in JunB degradation. This IL-4 induces a memory-like phenotype in peripheral CD8(+) T cells that includes elevated expression of CD44, CD122, and Eomesodermin and decreased expression of CD49d. Thus, our data show that excess peripheral IL-4 is sufficient to cause an increase in the VM population. Our results suggest that VM and innate CD8(+) T cells may be more similar than previously appreciated.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Memória Imunológica/fisiologia , Interleucina-4/imunologia , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/citologia , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/imunologia , Integrina alfa4/genética , Integrina alfa4/imunologia , Subunidade beta de Receptor de Interleucina-2/genética , Subunidade beta de Receptor de Interleucina-2/imunologia , Interleucina-4/genética , Camundongos , Camundongos Knockout , Proteínas com Domínio T/genética , Proteínas com Domínio T/imunologia , Timo/citologia , Timo/imunologia , Fatores de Transcrição/genética , Fatores de Transcrição/imunologiaRESUMO
Although the pathways that permit IL-2 production and the full activation of T cells upon Ag encounter are fairly well defined, the negative regulatory circuits that limit these pathways are poorly understood. In this study, we show that the E3 ubiquitin ligase adaptor Ndfip1 directs one such negative regulatory circuit. T cells lacking Ndfip1 produce IL-2, upregulate IL-2Rα, and proliferate, in the absence of CD28 costimulation. Furthermore, T cells in mice lacking both Ndfip1 and CD28 become activated, produce IL-4, and drive inflammation at barrier surfaces. Ndfip1 constrains T cell activation by limiting the duration of IL-2 mRNA expression after TCR stimulation. Ndfip1 and IL-2 have a similar expression pattern, and, following TCR stimulation, expression of both Ndfip1 and IL-2 requires the activity of NFAT and Erk. Taken together, these data support a negative regulatory circuit in which factors that induce IL-2 expression downstream of TCR engagement also induce the expression of Ndfip1 to limit the extent of IL-2 production and, thus, dampen T cell activation.