Role of the MHC class II transactivator in CD4 T cell differentiation.

The MHC Class II Transactivator, CIITA, is a master regulator of genes involved in antigen presentation. CIITA is primarily expressed in antigen presenting cells, so its function in T cells was not well understood. We studied the role of CIITA in CD4 T cell differentiation using both CIITA deficient mice (CIITA-/-) and transgenic mice ( CIITA Tg) expressing human CIITA. CIITA-/- Th1 cells expressed the Th2 cytokines IL-4, IL-5, and IL-13, in addition to normal levels of the Th1 cytokine IFN-gamma. Th2 differentiation was not affected. CIITA-/- Th1 cells secreted Th2 cytokines independent of exogenous IL-4, and with the same kinetics as control Th2 cells. IL-4 expression was due to cells producing IL-4 alone, as well as cells producing IL-4 and IFN-gamma simultaneously. The CIITA-/- Th1 phenotype was stable, and Th2 cytokine secretion was maintained despite multiple rounds of Th1-inducing stimulation. GATA-3 protein expression was partially responsible for the CIITA-/- Th1 phenotype, because anti-sense GATA-3 reduced Th2 cytokine expression at least 50% from transduced CIITA-/- Th1 cells. CIITA Tg CD4 T cells displayed a similar cytokine secretion pattern as CIITA-/- CD4 T cells. Th2 cytokine expression was due to an intrinsic property of CIITA Tg CD4 T cells, not NKT cells or Th2 effector/memory cells. GATA-3 protein was expressed by CIITA Tg Th1 cells, but neither Stat6 nor IL-4 was required by CIITA Tg CD4 T cells to express Th2 cytokines. Unimmunized CIITA Tg mice had elevated levels of serum IgE, suggestive of high IL-4 levels in vivo. There was a ten fold increase in both IL-4 producing thymocytes and naive CD4 T cells from CIITA Tg mice compared to control cells, indicating that CIITA expression predisposes CD4 T cells to express Th2 cytokines. This could occur by alterations in the chromatin structure of Th2 cytokine genes, or changes in the signaling thresholds required for their expression. Taken together, the proper expression of CIITA is critical in regulating Th1/Th2 differentiation and, consequently, the host immune response.Ph.D.Health and Environmental SciencesImmunologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/125731/2/3208530.pd