RESUMO
Cytokine driven or "bystander" proliferation of T cells occurs in vivo independently of major histocompatibility complex-T cell receptor interactions. This process may be important for supporting T cell homeostasis and facilitating T cell responses to microbial antigens, and may involve the cytokine interleukin (IL)-15. In this study, we find that IL-15Ralpha-deficient (IL-15Ralpha(-/-)) mice fail to undergo poly I:C or IL-15 driven bystander proliferation of CD8(+) T cells. Surprisingly, IL-15Ralpha(-/-) CD8(+) T cells proliferate in response to poly I:C when adoptively transferred into normal mice, and normal CD8(+) T cells fail to proliferate in IL-15Ralpha(-/-) mice. Normal mice reconstituted with IL-15Ralpha(-/-) bone marrow cells also fail to exhibit bystander responses. Thus, CD8(+) T cell independent IL-15Ralpha signals from radiation sensitive hematopoietic cells are likely required for bystander responses. Moreover, normal CD8(+) T cells proliferate in IL-15Ralpha(-/-) mice after treatment with IL-15. Therefore, IL-15Ralpha signals may mediate a positive feedback loop involving the further physiological production of IL-15. These findings provide new insights into how IL-15Ralpha supports memory phenotype CD8(+) T cell proliferation, and suggest novel mechanisms by which memory CD8(+) T cells are maintained in vivo.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Receptores de Interleucina-2/imunologia , Transdução de Sinais/imunologia , Transferência Adotiva , Animais , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Divisão Celular , Células Cultivadas , Feminino , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/imunologia , Células-Tronco Hematopoéticas/efeitos da radiação , Indutores de Interferon/farmacologia , Interleucina-15/imunologia , Interleucina-15/farmacologia , Células Matadoras Naturais , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Poli I-C/farmacologia , RNA Mensageiro , Tolerância a Radiação , Receptores de Interleucina-15 , Receptores de Interleucina-2/genéticaRESUMO
A20 is a cytoplasmic zinc finger protein that inhibits nuclear factor kappaB (NF-kappaB) activity and tumor necrosis factor (TNF)-mediated programmed cell death (PCD). TNF dramatically increases A20 messenger RNA expression in all tissues. Mice deficient for A20 develop severe inflammation and cachexia, are hypersensitive to both lipopolysaccharide and TNF, and die prematurely. A20-deficient cells fail to terminate TNF-induced NF-kappaB responses. These cells are also more susceptible than control cells to undergo TNF-mediated PCD. Thus, A20 is critical for limiting inflammation by terminating TNF-induced NF-kappaB responses in vivo.
Assuntos
Apoptose , Proteínas I-kappa B , Inflamação/fisiopatologia , NF-kappa B/metabolismo , Proteínas/fisiologia , Fator de Necrose Tumoral alfa/farmacologia , Animais , Caquexia/patologia , Caquexia/fisiopatologia , Células Cultivadas , Cisteína Endopeptidases , DNA/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Fibroblastos/metabolismo , Marcação de Genes , Inflamação/patologia , Interleucina-1/farmacologia , Intestinos/patologia , Peptídeos e Proteínas de Sinalização Intracelular , Rim/patologia , Lipopolissacarídeos/imunologia , Fígado/patologia , Camundongos , Inibidor de NF-kappaB alfa , Proteínas Nucleares , Fosforilação , Proteínas/genética , Pele/patologia , Linfócitos T/citologia , Linfócitos T/metabolismo , Proteína 3 Induzida por Fator de Necrose Tumoral alfa , Dedos de ZincoRESUMO
The IL-15 receptor alpha subunit (IL-15Ralpha) mediates high-affinity binding of IL-15, a pleiotropic cytokine implicated in the development of innate immune cells. We have generated IL-15Ralpha null (IL-15Ralpha-/-) mice to understand the role of IL-15Ralpha in immune development and function. IL-15Ralpha-/- mice are markedly lymphopenic despite grossly normal T and B lymphocyte development. This lymphopenia is due to decreased proliferation and decreased homing of IL-15Ralpha-/- lymphocytes to peripheral lymph nodes. These mice are also deficient in natural killer cells, natural killer T cells, CD8+ T lymphocytes, and TCRgammadelta intraepithelial lymphocytes. In addition, memory phenotype CD8+ T cells are selectively reduced in number. Thus, IL-15Ralpha has pleiotropic roles in immune development and function, including the positive maintenance of lymphocyte homeostasis.
