People

Research Interests

Work in my lab focuses on CD4⁺ T lymphocyte activation and effector subset differentiation.

• The biological consequences for individual T cells of signaling induced by APC-derived membrane molecules after their transfer to T cells at the T-APC immunological synapse, a process termed “trogocytosis”;
• 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 in CD4 Effector Subset and Memory T Cell DIfferentiation

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 molecule leading to the formation of an ordered structure at the T-APC interface termed the immunological synapse. The synapse is involved in T cell signaling as well as the site for delivery of T cell effector functions. 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 are examining the biological significance of intercellular transfer of molecules from APC to T cells. We've shown that APC-derived molecules continue to engage their receptors on T cell and sustain intracellular sigaling within 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-gamma). 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 T_H2 phenotype. the trogocytosis-mediated signaling also can induce the conversion of polarized T_H1 cells toward a T_H2 phenotype.  We hypothesize that this may play an important role in control of immune responses - promoting TH2 and limiting potentially damaging T_H1 responses.

In addition to driving T_H2-associated gene expression patterns, we have also observed that trogycytosis-ediated signaling induces a cellular phenotype consistent with a second CD4 effector subset, the Bcl-6⁺IL-21⁺CXCR5⁺ follicular T helper cells (T_FH).  Our current work involves examining the potential for trogocytosis-mediated signaling to induce CD4 differentiation to a T_FH phentype and to analyze its impact on antibody responses in vivo.  

Finally, we are just beginning experiments to analyze whether trogocytosis and trogocytosis-associated signaling have a role in asymmetrical division and the development of memory T cells from naive precursors.  

Immunotoxicology of Atrazine

We are 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 CD4⁺ T lymphocyte proliferation and effector function.  In addition, we have shown that the frequency of Foxp3 positive regulatory T cells (Treg) doubles in atrazine-treated cultures. This is largely due to elevated levels of cAMP, as Atrazine is a potent phosphidiesterase inhibitor.  We have recently found that male and female T cells repsond differently to atrazine exposure.  Atrazine's other biochemical effect is to induce expression of aromatase, which converts androgens to estrogen. 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 on 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.