RESUMO
The microtubule-associated protein lissencephaly 1 (Lis1) is a key regulator of cell division during stem cell renewal and differentiation. In this study, we examined the role of Lis1 in T lymphocyte homeostasis and fate diversification in response to microbial infection. T cell-specific deletion of Lis1 resulted in depletion of the peripheral CD4(+) and CD8(+) T lymphocyte pool owing to a loss of homeostatic, cytokine-induced proliferation. In contrast, cognate Ag-triggered proliferation was much less affected, enabling Lis1-deficient CD8(+) T cells to differentiate into terminal effector cells in response to microbial infection. Strikingly, however, the specification of Lis1-deficient long-lived memory CD8(+) T lymphocytes was impaired due, in part, to an apparent failure to differentiate appropriately to IL-15. Taken together, these findings suggest that Lis1 plays an important role in T cell homeostasis and the generation of memory T lymphocytes.
Assuntos
1-Alquil-2-acetilglicerofosfocolina Esterase/imunologia , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Memória Imunológica , Proteínas Associadas aos Microtúbulos/imunologia , 1-Alquil-2-acetilglicerofosfocolina Esterase/genética , Animais , Linfócitos T CD4-Positivos/imunologia , Divisão Celular , Homeostase/imunologia , Imunofenotipagem , Interleucina-15/imunologia , Interleucina-7/imunologia , Listeria monocytogenes , Listeriose/imunologia , Ativação Linfocitária , Camundongos , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/genética , Transdução de Sinais , Timo/imunologiaRESUMO
Poly(I:C) is an adjuvant used for antitumor treatment and vaccines because of its prominent effects on CD8 T cells and NK cells. Poly(I:C) binds TLR3 and this interaction is thought to be central for driving cell-mediated immune responses. We investigated the importance of TLR3 in poly(I:C)-mediated endogenous CD8 T cell responses using the pathogenic T cell stimulant Staphylococcus aureus enterotoxin A. While the responsive CD8 T cells expanded comparably in both wild-type and TLR3(-/-) mice, differentiation of effector CD8 T cells was enhanced by poly(I:C) in the TLR3(-/-) mice. A higher percentage of Ag-specific CD8 T cells became IFN-gamma and TNF-alpha producers in the absence of TLR3 signaling. Consistent with this boosted response was the observation that TLR3-deficient cells synthesized less IL-10 compared with TLR3-sufficient cells in response to poly(I:C). Ultimately, however, the fundamental mechanism of CD8 effector T cell differentiation through the TLR3-independent pathway was shown to be completely IFN-alpha/beta-dependent. Administration of IFN-alpha/beta-neutralizing Abs abolished the poly(I:C) effects in TLR3(-/-) mice. These findings reveal specific roles of how dsRNA receptors shape CD8 T cell responses, which should be considered as poly(I:C) is authenticated as a therapeutic adjuvant used in vaccines.
