UCSF

CD4+ T cells can take on a wide variety of effector phenotypes. Over the past 10 years, many different transcription factors have been identified that direct CD4+ T cell subphenotypes by initiating and sustaining unique transcriptional programs. Below, I show that expression of the transcription factor Tbx21 (T-bet) is necessary for diabetes in the NOD mouse. Expression of the transcription factor in both T cells and antigen presenting cells is necessary for disease in adoptive transfer models of autoimmune diabetes. Further, I show that Tbx21-/- regulatory T cells are competent to prevent diabetes in NOD.Cd28 -/- mice, which have greatly reduced Treg levels. Like Tbx21, CD28 is also critical for T cell activation and effector T cell differentiation. In an attempt to further understand the effect of CD28 ligation on effector cell activation, I activated naive human CD4+ T cells and measured global transcriptional changes by using microarray analysis. I found that at 4 hours after activation, CD28 ligation mostly amplified the changes initiated by TCR ligation. However, by 24 hours after activation, CD28 ligation was necessary to prevent global transcriptional quiescence. From these microarray data, I identified the transcription factor Bhlhe40 as a highly CD28-dependent gene. I show that the transcription factor is necessary for CD28 costimulation-dependent phenotypes such as CD25 expression in Jurkat T cells and IL-2 expression in primary mouse CD4+ T cells. Thus, I have identified a novel role for Bhlhe40 in CD28 costimulation during T cell activation and demonstrated a mechanism for the qualitative effects of CD28 costimulation.