Infant T cells exhibit increased TCR signaling and proliferation to respiratory infection

Abstract

Abstract Infants are highly susceptible to respiratory infections and frequently experience recurrent episodes. Our previous study demonstrated that tissue resident memory T cells (TRM), which are critical in mediating long-term protection against pathogens, are reduced in infant mice compared to adult mice after influenza infection. However, the underlying mechanisms for reduced TRM generation in infants is still unknown. Our preliminary data show that infant T cells have enhanced TCR sensitivity leading to increased activation compared to adult T cells and thus are biased towards effector differentiation at the expense of memory formation. We show that infant OVA-specific (OTII) T cells exhibit lower T cell activation threshold for proliferation and enhanced sensitivity for low does of antigen. Infant T cells express higher levels of CD69 and CD25 with a greater induction of Nur77, a direct indicator of TCR signal strength, at peptide doses that fail to fully activate adult T cells. Co-transfer of infant and adult OTII T cells into a congenic host resulted in infant T cells dominating the effector response in the lungs (at a ratio of 3:1) after primary influenza challenge. At the peak of infection, infant effector T cells also expressed lower levels of TCF1 and Bcl-2, indicating transcriptional bias for terminal effector differentiation with reduced survival. Moreover, infant derived effector and memory T cells express lower levels of CD5, suggesting enhanced survival of lower affinity T cells after influenza infection. Taken together, these results show that enhanced sensitivity for antigenic stimulation promotes cell intrinsic mechanisms that govern decreased potential of infants to form durable and functional lung TRM.