Anti-microbial T cell responses play a major role in determining the outcome of infection. Chronic infections are often distinguished by T cell responses that are not able to fully eliminate the pathogen. The mechanisms that explain this failure of T cell effector responses are only beginning to be understood. During the current funding period, we have used the lymphocytic choriomeningitis virus (LCMV) model to investigate how the PD-1 pathway regulates T cell responses during chronic infection. We have found that the PD-1 pathway has multifaceted roles in protective immunity. We discovered that in addition to PD-L1, PD-L2 limits responses of exhausted T cells. We also have shown that PD-L1 has distinct roles on hematopoietic and non- hematopoetic cells during chronic infection. However, we lack a mechanistic understanding of PD-L1 and PD-L2 functions on specific cell types. A major goal of this proposal is to elucidate mechanisms by which PD-1 and its ligands regulate CD8 T cell exhaustion, issues of fundamental and translational importance, given the therapeutic promise of this pathway. In addition, we have discovered a new function for the PD-1 pathway in protective immunity. We have identified a role for PD-1 in regulating humoral immunity by inhibiting the generation and function of T follicular regulatory cells. Thus, we will not only address how the PD-1 pathway regulates CD8 T cell exhaustion, but also how it controls humoral immunity. In addition, we will study roles of two novel coinhibitory molecules identified by PPG investigators in anti-microbial immunity: repulsion guidance molecule b (RGMb) and protein C receptor (PROCR). Dr. Freeman (Core B) identified RGMb as a second binding partner for PD-L2. The rescue of T cell exhaustion in PD-L2 deficient mice leads us to study RGMb function during chronic infection. Dr. Kuchroo (PI, Project 3) has identified protein C receptor (PROCR) as a novel coinhibitory molecule;in collaboration we have found that PROCR is highly expressed on exhausted CD8 T cells. We will study if PROCR regulates T cell exhaustion. Our main hypothesis is that PD-1 pathway members and PROCR regulate protective immunity during acute and chronic infections. To test this hypothesis, our Specific Aims are to: 1) Analyze how PD-1 and its ligands regulate humoral immunity during acute mucosal/localized viral infection (influenza) versus systemic infection (LCMV). 2) Investigate roles of the PD-1 and PROCR pathways in controlling exhausted CD8 T cells during chronic LCMV infection. Our goals are to determine how to optimally modulate the PD-1 and PROCR pathways therapeutically in chronic infection, and develop new strategies to promote protective immunity during acute viral infections.
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| Juchem, Kathryn W; Sacirbegovic, Faruk; Zhang, Cuiling et al. (2018) PD-L1 Prevents the Development of Autoimmune Heart Disease in Graft-versus-Host Disease. J Immunol 200:834-846 |
| Priyadharshini, Bhavana; Loschi, Michael; Newton, Ryan H et al. (2018) Cutting Edge: TGF-? and Phosphatidylinositol 3-Kinase Signals Modulate Distinct Metabolism of Regulatory T Cell Subsets. J Immunol 201:2215-2219 |
| Porichis, Filippos; Hart, Meghan G; Massa, Alexandra et al. (2018) Immune Checkpoint Blockade Restores HIV-Specific CD4 T Cell Help for NK Cells. J Immunol 201:971-981 |
| LaFleur, Martin W; Muroyama, Yuki; Drake, Charles G et al. (2018) Inhibitors of the PD-1 Pathway in Tumor Therapy. J Immunol 200:375-383 |
| Chaudhri, Apoorvi; Xiao, Yanping; Klee, Alyssa N et al. (2018) PD-L1 Binds to B7-1 Only In Cis on the Same Cell Surface. Cancer Immunol Res 6:921-929 |
| Ahn, Eunseon; Araki, Koichi; Hashimoto, Masao et al. (2018) Role of PD-1 during effector CD8 T cell differentiation. Proc Natl Acad Sci U S A 115:4749-4754 |
| Wu, Yongxia; Schutt, Steven; Paz, Katelyn et al. (2018) MicroRNA-17-92 is required for T-cell and B-cell pathogenicity in chronic graft-versus-host disease in mice. Blood 131:1974-1986 |
| Gartlan, Kate H; Bommiasamy, Hemamalini; Paz, Katelyn et al. (2018) A critical role for donor-derived IL-22 in cutaneous chronic GVHD. Am J Transplant 18:810-820 |
| Hippen, Keli L; Loschi, Michael; Nicholls, Jemma et al. (2018) Effects of MicroRNA on Regulatory T Cells and Implications for Adoptive Cellular Therapy to Ameliorate Graft-versus-Host Disease. Front Immunol 9:57 |
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