*Purpose: Assess the roles of T Follicular Helper and Regulatory cells in controlling pathogenic donor-specific antibodies (DSA) and antibody-mediated rejection(AbMR) during kidney transplantation.

*Methods: Here we developed novel mouse models to study the roles of Tfh and Tfr cells in pre-clinical models of allo-sensitization and kidney transplantation. We developed a “Tfh-deleter” mouse to specifically delete Tfh cells during the distinct stages of transplantation. Also, we developed a “Tfr-deleter” mouse to delete Tfr cells during distinct stages of transplantation.

*Results: Using the Tfh-deleter mouse, we found that Tfh cells have essential roles early during alloantigen exposure to induce potent DSA, even in settings of minimal Tfh cell expansion. We also found that Tfh cells have essential roles in regulating long-term memory B cell responses to alloantigens. Using the Tfr-deleter mouse, we found that Tfr cells regulate DSA production after alloantigen exposure and control long-term allospecific B cell responses. Currently, we are conducting pre-clinical kidney transplant studies to investigate the effects of Tfh and Tfr cells in modulating DSA and Antibody-Mediated Rejection.

*Conclusions: We found that Tfh and Tfr cells have key roles in regulating AbMR in the context of allo-sensitization and kidney transplantation. Our studies reveal therapeutic strategies to target these cells to limit pathology associated with AbMR.

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