ITK regulates the dynamics of CD8+ T cell homeostatic proliferation in lymphopenic environment (P1296)

Abstract

Abstract Tec family kinase ITK is an essential regulator of T cell development and function. The absence of ITK leads to spontaneous acquisition of innate memory phenotype (IMP) in CD8+ T cells, shown to be induced by bystander-derived IL-4. CD8+ T cells undergone homeostatic proliferation (HP) in lymphopenic conditions share similar memory markers with IMP CD8+ T cells. To examine the role of ITK during CD8+ T cell HP, we compared naïve CD8+ T cells from WT and Itk-/- OTI-Rag-/- transgenic mice. We found that they had similar CD44loCD122- naïve phenotype, but naïve Itk-/- T cells exhibited increased Eomes, KLF2, FoxO3, Bim, Blimp-1 and decreased Bcl-6 mRNA expression. When transferred into lymphopenic Rag-/- recipients, Itk-/- naïve CD8+ T cells exhibited rapid early expansion, giving rise to > 10 fold expansion over that of WT CD8+ T cells by 10 days post-transfer, which was followed by massive retraction with failure to sustain a plateau as seen in WT. The absence of ITK during HP resulted in defects in expression of cytokine receptors and Bcl-2, accompanied by enhanced apoptosis and Fas expression. These data indicate an important role of ITK in regulating the dynamics and maintenance of CD8+ T cells during HP, likely by regulating the expression of cytokine receptors required for sustained survival of these cells. This work suggests that targeting the ITK pathway may allow manipulation of CD8+ T cell number and function in lymphopenic conditions due to infection or irradiation.