Shared and distinct transcriptional programs underlie the hybrid nature of iNKT cells

Invariant natural killer T (iNKT) cells are innate-like T lymphocytes that act as critical regulators of the immune response. To better characterize this population, we profiled iNKT cell gene expression during ontogeny and in peripheral subsets as part of the Immunological Genome Project (ImmGen). High-resolution comparative transcriptional analyses defined developmental and subset-specific iNKT cell gene expression programs. In addition, iNKT cells were found to share an extensive transcriptional program with natural killer (NK) cells, similar in magnitude to that shared with major histocompatibility complex (MHC)-restricted T cells. Strikingly, the NK- iNKT program also operated constitutively in γδT cells and in adaptive T cells following activation. Together, our findings highlight a core effector program regulated distinctly in innate and adaptive lymphocytes

Shared and distinct transcriptional programs underlie the hybrid nature of iNKT cells

Invariant natural killer T cells (iNKT cells) are innate-like T lymphocytes that act as critical regulators of the immune response. To better characterize this population, we profiled gene expression in iNKT cells during ontogeny and in peripheral subsets as part of the Immunological Genome Project. High-resolution comparative transcriptional analyses defined developmental and subset-specific programs of gene expression by iNKT cells. In addition, we found that iNKT cells shared an extensive transcriptional program with NK cells, similar in magnitude to that shared with major histocompatibility complex (MHC)-restricted T cells. Notably, the program shared by NK cells and iNKT cells also operated constitutively in γδ T cells and in adaptive T cells after activation. Together our findings highlight a core effector program regulated distinctly in innate and adaptive lymphocytes

CD4(+)-T-Cell Effector Functions and Costimulatory Requirements Essential for Surviving Mucosal Infection with Citrobacter rodentium

Citrobacter rodentium causes an attaching and effacing infection of the mouse colon. Surprisingly, protective adaptive immunity against this mucosal pathogen requires a systemic T-cell-dependent antibody response. To define CD4(+) T-cell effector functions promoting this systemic defense of infected epithelial surfaces, studies were undertaken in weaning-age mice lacking costimulatory molecules CD28 or CD40L or cytokines gamma interferon (IFN-γ) or interleukin-4 (IL-4). Adoptive transfer of CD4(+) T cells from wild-type, CD28(−/−), CD40L(−/−), or IFN-γ(−/−) donors to CD4(−/−) recipients delineated functions of these CD4(+) T-cell-expressed molecules on the outcome of infection. Wild-type and IL-4(−/−) mice successfully resolved infection, while 70% of IFN-γ(−/−) mice survived. In contrast, all CD28(−/−) mice succumbed during acute infection. While fewer than half of CD40L(−/−) mice succumbed acutely, surviving mice failed to clear infection, resulting in progressive mucosal destruction, polymicrobial sepsis, and death 1 to 2 weeks later than in CD28(−/−) mice. Downstream of CD28-mediated effects, CD4(+) T-cell-expressed CD40L proved essential for generating acute pathogen-specific immunoglobulin M (IgM) and early IgG, which reduced pathogen burdens. However, deficiency of CD4(+) T-cell-expressed IFN-γ did not adversely impact survival or development of protective antibody in adoptively transferred CD4(−/−) recipients, though it impacted Th1 antibody responses. These findings demonstrate that CD4(+) T-cell-expressed CD40L promotes the rapid production of protective systemic antibody during acute infection, while deficiencies of IL-4 or of CD4(+) T-cell-expressed IFN-γ can be overcome. These findings have important implications for understanding the role of T-helper-cell responses during infections involving mucosal surfaces