GRANZYME A+ CD4 T CELLS ARE CRITICAL MEDIATORS OF INTESTINAL DISEASE

The gastrointestinal tract encounters a variety of foreign antigens such as digested food, pathogens and normal bacterial flora. The high immune challenge by those antigens should be regulated properly by tolerating non-pathogenic antigens and responding to pathogenic antigens. CD4+ T cells have been identified as key player orchestrating the immune responses by secreting pro (IFN-𝛾, IL-17) or anti-inflammatory cytokines (IL-10). Our lab identified a potentially novel subset of CD4+ T cells that produces serine protease granzyme A (GrA) rather than other cytokines, but partially co-produce IFN-𝛾. GrA+ CD4 T cells reside specifically within the small intestine under the steady state and produce GrA in a STAT3-dependent manner. 

Since the GrA+ CD4 T cells exist in the intestine more than any other tissues, we asked if this cell type contributes to regulation of gut inflammation in some types of diseases such as Graft- Versus-Host-Disease (GVHD) and Inflammatory Bowel Disease (IBD). GVHD occurs in patients who receive hematopoietic cell transplantation to treat hematological malignancies (i.e. leukemia and lymphoma). However, when the donor T cells recognize the host tissues as foreign antigen, it induces immune responses and causes inflammation and organ damage in many tissues, including the intestines. In the IBD patients, CD4 T cells are critical to induce intestinal inflammation, but it is less clear which CD4 T cell subsets play a major role in the induction of inflammation. 

In our GVHD mouse model, increased numbers of GrA+ CD4 T cells were detected from intestine and liver as compared to control syngeneic mice. In addition, Gzma -/- CD4 T cells recipient GVHD mice showed less severity of disease and mortality compared to WT CD4 T cells received mice. These results suggest that GrA+ CD4 T cell is associated with exacerbating inflammation of GVHD disease. In our IBD mouse model, GrA+ CD4 T cells were detected from inflamed gut tissues and the absence of GrA+ CD4 T cells showed reduced disease progression. In the context of our data, GrA+ CD4 T cells is a novel and potentially important CD4 T cell subset residing in intestine and playing an important role in immunological homeostasis in gut.