Novel pathways in T lymphocyte differentiation and function

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The ability to generate high-affinity antibodies to diverse infectious agents (i.e. humoral immunity) is a fundamental property of the vertebrate immune system and ensures host survival. The humoral immune response requires highly coordinated interactions between B lymphocytes (which possess antibody-producing potential) and "helper" T cells. These interactions are mediated by a subset of helper T cells termed T follicular helper (Tfh) cells that provide direct help to B cells through provision of membrane-bound co-stimulatory molecules and secretion of polarizing cytokines. We have previously shown that Tfh cells provide critical sources of interleukin (IL)-4 and IL-21 required for the generation of humoral immune responses in the context of immunization (King et al, Nature Immunology, 2012) and parasitic helminth infection (King and Mohrs, Journal of Experimental Medicine, 2009). This proposal builds on these findings to identify previously undescribed molecules and signaling pathways that specifically control T cell differentiation and function. To discover molecules uniquely expressed by Tfh cells, we performed preliminary experiments using microarray technology comparing this subset to other CD4+ T cell subsets isolated from the inflamed mesenteric lymph nodes of mice infected with an intestinal helminth. Our results indicate that Tfh cells express high levels of CD109 compared to other CD4+ T cells. CD109 is a glycophosphatidylinositol-anchored protein with unknown function in the immune system. Functional studies using keratinocytes have demonstrated that CD109 acts as a negative regulator of transforming growth factor (TGF)-b1 signaling, a cytokine that dramatically influences T effector cell differentiation. Preliminary results from my laboratory indicate that key TGF-b1 target genes such as SMAD7 are downregulated in Tfh cells, findings consistent with the idea that CD109 is also negatively regulating this signaling pathway in T cells. In addition, CD109 has been been shown to regulate STAT3, a transcription factor that promotes Tfh cell differentiation as well as other T effector subsets. Thus, an in-depth analysis of CD109 in T cell biology and its potential relationship to TGF-b1 and STAT3-dependent signaling in lymphocytes is warranted. In this application, we propose a research program to elucidate the function of CD109 in T cell activation and its specificity in controlling T cell differentiation and function by pursuing 3 specific objectives: 1. Identify the requirements for CD109 expression by CD4+ T cells. 2. Determine how CD109 impacts CD4+ T cell activation and differentiation. 3. Identify CD109 binding partners in activated CD4+ T cells. Understanding the function of CD109 in T cell differentiation and/or function will provide new insight into the molecular mechanisms controlling this important immune cell population.