| Description |
During acute infection, a CD4+ T cell response begins with the interaction between the T cell receptor (TCR) and its cognate antigen presented by major histocompatibility complex (MHC) class II on antigen presenting cells. The nature of these interactions impacts various aspects of T cell fate. Here we find that TCR signals influence the generation of Th1 memory cells. The transition of activated CD4+ T cells from effector to memory is associated with a significant decrease in TCR repertoire diversity. Particularly, a slow dissociation rate of TCR-antigen interactions, but not TCR avidity, corresponds to memory potential. Thus, long-lived TCR interactions with antigen during priming are a determinative factor in promoting Th1 memory differentiation. Once generated, memory T cells are maintained at stable levels. However, CD4+ memory T cells gradually decline in some mouse models of acute infection. We find that heterologous rechallenge of Th1 memory cells with a pathogen sharing only a CD4+ T cell epitope, which allows for robust boosting of memory T cells without rapid antigen clearance, leads to the generation of highly stable secondary Th1 memory cells that do not decline. Importantly, enhanced memory stability corresponds to the acquisition of high antigen sensitivity, often referred to as functional avidity, at the peak of the recall response. In contrast, homologous rechallenge of Th1 memory cells, where memory iv cells are weakly stimulated due to the limited antigen persistence, does not enhance function and stability of secondary Th1 cells. Upon heterologous rechallenge, the recall response of Th1 memory cells is characterized by the early emergence of secondary responders with high functional avidity, followed by functional avidity decay to the level similar to the parent memory cells. Unexpectedly, responding secondary effectors progressively lose their functional avidity when secondary infection is prolonged, which corresponds to the generation of poorly stable secondary memory cells. Functional avidity decay requires an extended period of both antigen presentation and infectious inflammation and correlates with the diminished magnitude of TCR signaling. Together, the recall response of Th1 memory cells is functionally dynamic, and the nature of secondary stimulation influences function and stability of secondary Th1 cells. |
