TCR signal strength and antigen affinity independently modulate CD8+ memory T cell development

Abstract

Abstract CD8+ T cells play a critical role in adaptive immunity by maintaining the ability to differentiate into CD8+ memory T cells, which provide the basis of protective immunity. During an intracellular infection, CD8+ T cells pass through several characteristic phases before becoming mature memory cells. Initial antigen stimulation causes naïve CD8+ T cells to clonally expand and differentiate into short-lived effector cells (SLECs). Subsequently, SLECs undergo a contraction phase to give rise to memory precursor effector cells (MPECs); 5–10% of the MPECs survive the initial contraction phase and further develop into CD8+ memory T cells. We have shown that the non-receptor tyrosine kinase Itk, which regulates TCR signal strength, can significantly suppress CD8+ memory T cell development. We hypothesize that TCR signal strength, regulated by Itk, intersects with antigen affinity to modulate the development of SLECs and MPECs, leading to an increased proportion of memory CD8+ T cells. Utilizing Itk deficient OT-1 TCR transgenic mice, which carry CD8+ T cells specific for the Ovalbumin protein, an adoptive transfer model was established to exam the influence of TCR signal strength and antigen affinity in the development of CD8+ memory T cells. Our findings suggest that TCR signal strength and affinity independently contribute to CD8+ memory T cell development. Our data reveals that reducing both antigen affinity and TCR signal strength leads to enhanced and accelerated antigen-mediated proliferation and development of memory cells, and enhanced secondary expansion of these memory cells. In sum, our data suggests that TCR signal strength and antigen affinity are independent parameters that may be used to tune vaccine development.