WORK IN THE WETZEL LAB FOCUSES ON THE ACTIVATION AND SUBSET DIFFERENTIATION OF CD4+ T LYMPHOCYTES.
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The biological consequences for individual T cells after the capture of APC membrane fragments from T-APC immunological synapse, a process termed “trogocytosis
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The impact of the herbicide Atrazine on the activation of CD4+ T cells and the mechanism underlying a significant increase in Foxp3+ regulatory T cells.
The Role of Trogocytosis-Mediated Signaling In Effector Subset and Memory T Cell Development
CD4+ T lymphocytes recognize antigenic peptide fragments presented on the surface of antigen presenting cells (APC) by major histocompatiblility complex (MHC) class II proteins. This initial antigen recognition is followed by large-scale spatial and temporal molecular rearrangements of plasma membrane proteins and intracellular signaling molecules leading to the formation of an ordered structure at the T-APC interface termed the immunological synapse. Our lab has previously shown that that molecules from the APC are transferred to the T cell at the immune synapse in a process called trogocytosis. We have previously reported that these trogocytosed APC-derived molecules continue to engage their receptors on T cell and sustain intracellular signaling within the T cell. We have termed this phenomenon Trogocytosis-Mediated Signaling.
We are examining the biological significance of trogocytosis-mediated signaling for the T cell. This signaling leads to the selective survival of these T cells in culture and drives the production of some effector cytokines (e.g. IL-4, IL-6, IL-21), while inhibiting production of other cytokines (e.g. IFN-γ). Our work suggests that trogocytosis-mediated signaling ultimately induces expression of transcription factors and effector cytokines within the cells consistent with differentiation of cells towards a TH2 phenotype. The trogocytosis-mediated signaling also can induce the conversion of polarized TH1 cells toward a TH2 phenotype. We hypothesize that this may play an important role in control of immune responses - promoting TH2 and limiting potentially damaging TH1 responses.
In addition to driving TH2-associated gene expression patterns, we have also observed that trogocytosis-mediated signaling induces a cellular phenotype consistent with a second CD4 effector subset, the Bcl-6+IL-21+CXCR5+ follicular T helper cells (TFH). Our current work involves examining the potential for trogocytosis-mediated signaling to induce CD4 differentiation to a TFH phenotype and to analyze its impact on antibody responses in vivo.
Finally, we are beginning experiments to analyze whether trogocytosis and trogocytosis-mediated signaling have a role in asymmetrical division and the development of memory CD4+ T cells from naive precursors.
Immunotoxicity of Atrazine
We are also examining the impact on Atrazine on the activation and differentiation of CD4+ T cells. Atrazine is a very widely applied herbicide that the USGS estimates contaminates 70% of the ground water in the US. It has been linked to birth defects, cancer, immune developmental defects and modulation of immune cell effector functions. We have shown that Atrazine inhibits lymphocyte proliferation and lymphocyte effector function. In addition, we have shown that the frequency of Foxp3 positive regulatory T cells (Treg) doubles in atrazine-treated cultures. We have recently found that male and female T cells respond differently to atrazine exposure. We are currently examining the impact of Atrazine-induced elevated estrogen on the induction of Tregs and Atrazine-associated inhibition of T cell activation.
We are also examining whether the effects of atrazine on T cell function and fate are directly upon the T cell or whether it is working via altering antigen presenting cell phenotype/activity.
Our ultimate goal with this project is to examine whether in vivo atrazine exposure alters or limits an in vivo immune response to tumors or infectious disease.