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 disease as well as important information for the generation of functional Tregs ex vivo, which could be optimally suited to specifically target SLE.
These studies will delineate new molecular pathways, which, if deregulated, can lead to the development of Systemic Lupus Erythematosus (SLE), a prototypical systemic autoimmune disorder characterized by hypergammaglobulinemia, autoantibody production, and multi-organ involvement. In particular, these studies will provide critical insights into the role of aberrant translational mechanisms in this disease, a new and important area of biology that has great clinical and therapeutic potential. The work outlined in this proposal will also dissect the interplay between distinct subsets of regulatory T cells in SLE providing insights into whether presence of different Treg subsets can contribute to the known heterogeneity of this disease. This information will be critical for the development of optimal Treg-based therapeutics for the treatment of SLE.
| Manni, Michela; Gupta, Sanjay; Ricker, Edd et al. (2018) Regulation of age-associated B cells by IRF5 in systemic autoimmunity. Nat Immunol 19:407-419 |
| Manni, Michela; Ricker, Edd; Pernis, Alessandra B (2017) Regulation of systemic autoimmunity and CD11c+ Tbet+ B cells by SWEF proteins. Cell Immunol 321:46-51 |
| Yi, Woelsung; Gupta, Sanjay; Ricker, Edd et al. (2017) The mTORC1-4E-BP-eIF4E axis controls de novo Bcl6 protein synthesis in T cells and systemic autoimmunity. Nat Commun 8:254 |
| Ricker, Edd; Chowdhury, Luvana; Yi, Woelsung et al. (2016) The RhoA-ROCK pathway in the regulation of T and B cell responses. F1000Res 5: |
