CD49d marks Th1 and Tfh-like antigen-specific CD4+ T cells during Plasmodium chabaudi infection

Upon activation, specific CD4(+) T cells up-regulate the expression of CD11a and CD49d, surrogate markers of pathogen-specific CD4(+) T cells. However, using T-cell receptor transgenic mice specific for a Plasmodium antigen, termed PbT-II, we found that activated CD4(+) T cells develop not only to CD11a(hi)CD49d(hi) cells, but also to CD11a(hi)CD49d(lo) cells during acute Plasmodium infection. CD49d(hi) PbT-II cells, localized in the red pulp of spleens, expressed transcription factor T-bet and produced IFN-gamma, indicating that they were type 1 helper T (Th1)-type cells. In contrast, CD49d(lo) PbT-II cells resided in the white pulp/marginal zones and were a heterogeneous population, with approximately half of them expressing CXCR5 and a third expressing Bcl-6, a master regulator of follicular helper T (Tfh) cells. In adoptive transfer experiments, both CD49d(hi) and CD49d(lo) PbT-II cells differentiated into CD49d(hi) Th1-type cells after stimulation with antigen-pulsed dendritic cells, while CD49d(hi) and CD49d(lo) phenotypes were generally maintained in mice infected with Plasmodium chabaudi. These results suggest that CD49d is expressed on Th1-type Plasmodium-specific CD4(+) T cells, which are localized in the red pulp of the spleen, and can be used as a marker of antigen-specific Th1 CD4(+) T cells, rather than that of all pathogen-specific CD4(+) T cells.