Secondary stimulation of CD4 T cells generates an exhaustion phenotype

Abstract

Abstract Activated naïve T cells typically acquire effector functions over a 2–3 day period of differentiation in the secondary lymphoid organs, before migrating to the tissue sites to deliver effector functions. If the stimulating antigen is long lasting, as in the case of chronic infections, the T cells may undergo exhaustion, often through pathways involving co-inhibitory receptors such as PD1. Surprisingly, we find that a secondary and acute stimulation even short periods after the initial antigen encounter leads CD4+ T cells to exhibit properties of an exhausted phenotype. This is marked by the loss of proliferative potential and the upregulation of PD1. Naïve TCR-transgenic 5C.C7 T cells stimulated with their cognate peptide, proliferate rapidly between 2–4 days. Re-stimulation of these T cells on the 3rd day however, revealed a profound proliferative arrest accompanied by the rapid re-expression of PD1. The new levels of PD1 was proportional to the dose of re-stimulating antigen. This phenomenon was distinguished from Activation Induced Non-Responsiveness (AINR) as the 2nd stimulation arrested even the basal proliferation that was residual from the 1st antigen exposure. However, this is consistent with the property of effector T cell tuning that was previously described for effector T cells homing to tissue sites. We are currently examining the molecular machinery underlying this duality during T cell expansion to understand the paradoxical loss of T cell responsiveness to antigen during a primary effector response. These studies are expected to develop new approaches to not only improving primary T cell responses but also circumventing exhaustion during chronic microbial infections and tumors.