Upon infection, naive T lymphocytes proliferate and differentiate into highly specialized cell types to combat the pathogen: CD4+ T cells into specialized helper subsets and CD8+ T cells into armed effectors. Although the majority of the antigen specific T cells from both lineages will die as the immune response wanes, a few will survive indefinitely to establish memory populations, providing long-lived protection against reinfection. Transcriptional regulators of the E-protein and Id families are important arbiters of both T cell development in the thymus, and differentiation in response to infection. We and others, have shown that E/Id proteins cooperate to balance expression of genes that control CD8+ T cells throughout their differentiation, however, their role in the differentiation of CD4+ helper subsets has not been studied as extensively. My recent work uncovered a role for Id and E proteins in the differentiation of CD4+ T helper 1 (TH1) and T follicular helper (TFH) cells following infection. I found that that TH1 cells showed more robust Id2 expression than that of TFH cells, and depletion of Id2 via RNA-mediated interference increased the frequency of TFH cells. Furthermore, TH1 differentiation was blocked by Id2 deficiency, which led to E-protein-dependent accumulation of effector cells with

mixed characteristics during viral infection and severely impaired the generation of

TH1 cells following infection with Toxoplasma gondii. Finally, the TFH cell-defining

transcriptional repressor Bcl6 bound the Id2 locus, which provides a mechanism

for the bimodal expression of Id2 and reciprocal development of TH1 cells and TFH

cells. Investigation of Id3 revealed that naive CD4+ T cells expressed high levels

of Id3, which, when compared to TH1 cells, is maintained by TFH cells following

LCMV infection. I found that Id3 was required to restrict unchecked differentiation

of TFH and GC TFH cells. Lastly, I showed that expression of Id3 marks CD4+ T cells

with multipotent recall potential following LCMV infection. These studies inform

the functional relevance of E/Id proteins in CD4+ T cells, given the importance of

leveraging the recall capabilities of memory T cells to fight reinfection.