We have identified a subset of CD8+ cells programmed to inhibit activation and expansion of helper T (TH) cells through recognition of the class Ib MHC molecule Qa-1 (HLA-E in man). Mice that express a Qa-1 point mutation that disrupts binding of Qa-1 to the TCR/CD8 co-receptor of Treg develop dysregulated TFH responses and die of systemic autoimmune disease 9-12m after birth. Regulatory activity is mediated by <5% of CD8 T cells that express a diagnostic triad of surface receptors. We have also shown that the Helios transcription factor (TF) stabilizes the CD8 Treg genetic program and have recently identified the highly restricted T-cell receptor (TCR)?? repertoire that may mediate Ag-specific recognition by CD8 Treg. We use these findings to trace the development of this regulatory CD8 lineage and apply these insights towards development of novel therapeutic approaches to autoimmune disease. We propose here to test the premise that Qa-1-restricted CD8 Treg represent a unique regulatory lineage of CD8 cells that express a Helios-dependent genetic program and a restricted set of TCR specific for Qa-1/HA-E-associated self-peptides.
In Aim 1, we will define the contribution of the TCR to intrathymic CD8 Treg selection and differentiation using Ag-specific TCR knock-in (KI) and retrogenic mice that express a TCR specific for Qa-1-restricted self-peptides. This analysis will also allow dissection of the molecular requirements for thymic selection and differentiation of class Ib MHC-dependent CD8+ Treg. Single-cell transcriptome analysis will be used to define the relationship between TCR specificity for Qa-1?peptide ligands and shaping of the lineage-specific genetic program of Ag-specific CD8 Treg.
In Aim 2, we will define the contribution of the Helios TF to thymic and post-thymic differentiation of CD8 Treg. This approach will entail measurement of the impact of specific deletion of Helios at defined stages of Ag-specific CD8 Treg differentiation. The results from these studies and SA1 will provide a foundation for investigation of the interaction between Ag-specific CD8 Treg and target cells in disease settings (Aim 3). Here we will define the inhibitory interaction between Ag-specific CD8+ Treg and its target cells. Since Helios-dependent expression of NKG2D costimulatory receptors may be essential to CD8 Treg signaling, we will characterize the contribution of this costimulatory receptor to CD8 Treg activation by stress-associated Qa-1?Hsp60 and NKG2D ligands (NKG2D- L). Insight into this interaction will be applied to the design of nanoparticle-based therapeutic approaches to autoimmune disease.
According to the CDC, the prevalence of Rheumatoid Arthritis (RA) is predicted to rise from 52.5 million (2012) to 78 million by 2040, and affects all Americans from children to the elderly. We have made substantial progress in defining a regulatory pathway that can be utilized to inhibit progression of disease in a preclinical model of RA. We propose to utilize these insights to define the core properties of this pathway and apply this information to new therapeutic approaches to RA in a mouse model of this disease.
|Shen, Erxia; Wang, Qin; Rabe, Hardis et al. (2018) Chromatin remodeling by the NuRD complex regulates development of follicular helper and regulatory T cells. Proc Natl Acad Sci U S A 115:6780-6785|
|Yates, Kathleen; Bi, Kevin; Haining, W Nicholas et al. (2018) Comparative transcriptome analysis reveals distinct genetic modules associated with Helios expression in intratumoral regulatory T cells. Proc Natl Acad Sci U S A 115:2162-2167|
|Nakagawa, Hidetoshi; Sido, Jessica M; Reyes, Edwin E et al. (2016) Instability of Helios-deficient Tregs is associated with conversion to a T-effector phenotype and enhanced antitumor immunity. Proc Natl Acad Sci U S A 113:6248-53|
|Kim, Hye-Jung; Barnitz, R Anthony; Kreslavsky, Taras et al. (2015) Stable inhibitory activity of regulatory T cells requires the transcription factor Helios. Science 350:334-9|
|Alvarez Arias, Diana A; Kim, Hye-Jung; Zhou, Penghui et al. (2014) Disruption of CD8+ Treg activity results in expansion of T follicular helper cells and enhanced antitumor immunity. Cancer Immunol Res 2:207-16|
|Leavenworth, Jianmei W; Tang, Xiaolei; Kim, Hye-Jung et al. (2013) Amelioration of arthritis through mobilization of peptide-specific CD8+ regulatory T cells. J Clin Invest 123:1382-9|
|Holderried, Tobias A W; Lang, Philipp A; Kim, Hye-Jung et al. (2013) Genetic disruption of CD8+ Treg activity enhances the immune response to viral infection. Proc Natl Acad Sci U S A 110:21089-94|
|Kim, Hye-Jung; Wang, Xuan; Radfar, Soroosh et al. (2011) CD8+ T regulatory cells express the Ly49 Class I MHC receptor and are defective in autoimmune prone B6-Yaa mice. Proc Natl Acad Sci U S A 108:2010-5|
|Kim, Hye-Jung; Cantor, Harvey (2011) Regulation of self-tolerance by Qa-1-restricted CD8(+) regulatory T cells. Semin Immunol 23:446-52|
|Kim, Hye-Jung; Verbinnen, Bert; Tang, Xiaolei et al. (2010) Inhibition of follicular T-helper cells by CD8(+) regulatory T cells is essential for self tolerance. Nature 467:328-32|
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