Secondary CD4+ T cell effectors retain heterogeneity during recall responses but are functionally superior to primary effectors (163.8)

Abstract It is not known whether or how distinctions between secondary (2°) CD4+ T cell effectors, generated from memory precursors, and primary (1°) effectors, arising from naïve cells, contribute to protective recall responses. Here, we compare these two populations in vivo following influenza A virus infection (IAV). We show that 2° effectors are functionally superior to 1° effectors, and that their generation is critical to memory CD4+ T cell mediated protection against IAV. 2° effectors develop and migrate to infected lungs with similar kinetics, but 2° effectors accumulate in greater number and demonstrate enhanced multifunctional capabilities. The 2° effector response in the lung is a critical component of protection against influenza mediated by memory CD4+ T cells and upon transfer to unprimed hosts, 2° effectors are superior to 1° effectors at mediating protection. Transcriptome analysis indicates that 1° and 2° effectors responding in different organs share key genetic pattterns, however, 2° effectors possess unique gene signatures. Finally, by targeting differentially expressed surface molecules, we demonstrate specific regulation of 1° and 2° effector functions in vivo. Our approach provides novel insight into the regulation of effector CD4+ T cells during pathogen challenge and may reveal ideal candidates for manipulation with the goal of directing the generation of larger populations of multifunctional effectors in a variety of settings apart from IAV infection.