| The mammalian immune system is intricately regulated, allowing for potent pathogen-specific immunity to be rapidly activated in response to infection with a broad and diverse array of potential pathogens. Due to their ability to differentiate into distinct effector lineages, CD4 T cells significantly contribute to pathogen-specific adaptive immune responses. While the factors required for differentiation of CD4 T cells to an effector lineage have been well established, it is unclear to what degree CD4 T cells heritably commit to a specific lineage or retain functional plasticity in vivo. Our findings indicate that in response to Th1-polarizing bacterial or viral infections, 80--90% of responding polyclonal CD4 T cells became indelibly committed to the Th1 lineage. Commitment was nearly invariant in cells that proliferated extensively during priming, but perturbations to the extrinsic cytokine milieu or the pathogen's ability to enter the cytosol impeded commitment and promoted mixed and plastic Th1/Th17 memory responses. CD4 T cells expressing IFN-gamma during the effector stage displayed enhanced commitment to the Th1 lineage during the memory stage while acquisition of permissive chromatin marks at the Il17a locus in effector CD4 T cells predicted Th1/Th17 plasticity during memory.;In contrast to CD4 T cells, CD8 T cells inherently differentiate into IFN-gamma-producing effectors. However, under rare circumstances, CD8 T cells diverge to alternative effector lineages. We identified the signals necessary for deviation of CD8 T cells to an IL-17-producing lineage. Inhibition of type-I interferons and IL-12 during Listeria monocytogenes infection promoted IL-23-dependent production of IL-17 by antigen-specific CD8 T cells. While the addition of IL-23 in vitro was sufficient for some naive CD8 T cells to differentiate into IFN-gamma/IL-17 dual-producers, the combination of IL-6, TGF-beta and IL-23 enhanced IL-17 production by CD8 T cells, augmented ROR-gammat and ROR-alpha expression, and drastically reduced granzyme B and perforin expression.;Thus, a strong type-I polarizing environment promotes the development and maintenance of Th1 and cytotoxic T cells, but flexibility to deviate effector functions in response to alterations in the environment allows for T cells to combat a diverse array of pathogens. |
