Sepsis Mortality in CIITA Deficient Mice is Associated with Excessive Release of High-mobility Group Box 1

BACKGROUND: Down regulation of major histocompatibility complex class II transactivator (CIITA) has been identified as a major factor of immunosuppression in sepsis and the level of CIITA expression inversely correlates with the degree of severity. However, it has not been fully elucidated whether the lower expression of CIITA is a cause of disease process or a just associated sign. Here we determined whether the CIITA deficiency decreased survival rate using murine sepsis model. METHODS: Major histocompatibility complex class II (MHC-II) deficient, CIITA deficient and wild type B6 mice were subjected to cecal ligation puncture (CLP) surgery. CIITA and recombination activation gene (RAG)-1 double deficient mice were generated to test the role of lymphocytes in CIITA-associated sepsis progression. RESULTS: Sepsis mortality was enhanced in CIITA deficient mice, not by impaired bacterial clearance resulted from CD4 T cell depletion, but hyper-inflammatory response such as excessive release of a pro-inflammatory cytokine, high-mobility group box 1 (HMGB1). CONCLUSION: Our results demonstrate that CIITA deficiency affects the course of sepsis via the unexpected function of CIITA, regulation of cytokine release.

Overexpression of CIITA in T Cells Aggravates Th2-Mediated Colitis in Mice

The MHC class II transactivator (CIITA) is the master transcriptional regulator of genes involved in MHC class II restricted antigen presentation. Previously we suggested another role of CIITA in Th1/Th2 balance by demonstrating that forced expression of CIITA in murine T cells repressed Th1 immunity both in vitro and in vivo. However, the results were contradictory to the report that CIITA functioned to suppress the production of Th2 cytokine by CD4+T cells in CIITA deficient mice. In this study, we investigated the influence of constitutive expression of CIITA in T cells on Th2 immune response in vivo using murine experimental colitis model. In the dextran sodium sulfate-induced acute colitis, a disease involving innate immunity, CIITA transgenic mice and wild type control mice showed similar progression of the disease. However, the development of oxazolone-induced colitis, a colitis mediated by predominantly Th2 immune response, was aggravated in CIITA-transgenic mice. And, CD4+T cells from the mesenteric lymph node of CIITA-transgenic mice treated with oxazolone exhibited a high level of IL-4 secretion. Together, these data demonstrate that constitutive expression of CIITA in T cells skews immune response to Th2, resulting in aggravation of Th2-mediated colitis in vivo.

Delayed allograft rejection by the suppression of class II transactivator

We examined the effect of class II transactivator (CIITA) down-modulation on allograft rejection. To inhibit the function of CIITA, we constructed a series of CIITA mutants and found one exhibiting the dominant-negative effect on the regulation of major histocompatibility complex (MHC) class II expression. To test whether the CIITA dominant-negative mutant reduces immunogenecity, CIITA-transfected melanoma cells were injected into allogeneic host and assessed for immune evading activity against host immune cells. We demonstrated that the CIITA dominant-negative mutant allowed tumor nodules to develop earlier in the lung than control by this tumor challenge study. Furthermore, skin grafts deficient for CIITA also survived longer than wild-type in allogeneic hosts. Both the tumor challenge and skin graft studies suggest the inhibition of CIITA molecules in donor tissue would be beneficial to the control of allo-response.