ABSTRACT Despite significant advances in our understanding of the pathogenic mechanisms responsible for the development of Systemic Lupus Erythematosus (SLE) many patients with SLE continue to live with poorly controlled disease. A major roadblock in our ability to develop novel treatments for SLE is the significant heterogeneity that accompanies this disorder, which is partly due to the complexity of T helper and regulatory T cell subsets. Amongst TH subsets, TFH cells play a major role in lupus pathogenesis due to their crucial role in driving humoral responses. TFH cell development requires Bcl6 and overexpression of Bcl6 is sufficient to drive TFH differentiation indicating that tight control of Bcl6 expression is essential to ensure proper regulation of TFH cell numbers. Using mice lacking DEF6 and SWAP-70 (DKO mice), two members of a unique family of immune regulators whose absence leads to the spontaneous development of lupus, we have recently uncovered a new mechanism controlling the expression of Bcl6 and the expansion of TFH cells. Indeed DKO mice exhibit an accumulation of TFH cells due to aberrant translation of Bcl6. Increased translation of Bcl6 in DKO TH cells is the result of enhanced mTORC1 activation secondary to aberrant control of a pathway regulating the assembly of a raptor-p62-TRAF6 complex. A proteomic approach demonstrated that enhanced Bcl6 translation in DKO TH cells is accompanied by dysregulated expression of a selected number of proteins. In addition to cell-intrinsic abnormalities in TFH cells, imbalances in the coordinated development of TFH cells and its specialized effector Treg subset, follicular regulatory T (TFR) cells, can also promote autoimmunity. An analysis of the Treg population in DKO mice has revealed a defective expansion of TFR cells but a robust accumulation of non-TFR effector Tregs. In this proposal we will explore the hypothesis that an aberrant ability of TFH cells to employ translational mechanisms coupled with defects in the TFR cell subset can lead to systemic autoimmunity. We will also investigate the related hypothesis that while defects in TFR cells can fuel aberrant autoantibody production, the simultaneous expansion of non-TFR effector Tregs can help limit the tissue damage promoted by these autoAbs. Specifically we will: 1) Delineate the regulation and role of mTORC1-dependent translational programming in TFH cells, and 2) Dissect the pathways controlling effector Treg subsets in lupus. While transcriptional abnormalities in SLE have been extensively investigated, the impact of aberrant translational mechanisms on the function of lupus T cells has received little attention. These studies will thus provide critical information on a new area of investigation and potentially uncover novel targets for therapeutic intervention. A better understanding of the involvement of different Treg subsets in lupus could furthermore provide new insights into the heterogeneity that accompanies this disea...