We hypothesize that interaction ofT cell Immunoglobulin Mucin (TIM) proteins with their ligands regulates the aggressive and protective components of the allograft response. Both basic science and translational aspects are explored. Crucial to our proposal is knowledge that the potential to create peripheral transplant tolerance is negated in Tim-3 deficient mice and in wild type mice treated with blocking anti-Tim-3 mAb or Tim-3.Ig fusion proteins. Why? In the absence of the Tim-3-to-galectin-9 interaction, TH1 type alloimmune responses are not properly terminated and the TREG compartment does not expand. New experiments reveal that Tim-3 is expressed on CD4+ TH17 and CD8+ CTLs (Tc1) effector T cells as well as terminally differentiated TH1 cells. These findings serve to magnify the importance of the Tim-3-to-galectin-9 interaction in the effector T cell allograft response. Another Tim family member Tim-1 is expressed on all activated T cells and we have identified Tim-4 that is expressed on antigen presenting cells as the ligand for Tim-1. We have now identified antagonist .type anti-Tim-1 mAbs as well as agonist type anti-Tim-1 mAbs. The 3B3 agonist mAb and Tim-4.Ig, act as potent T cell co stimulants. In vivo administration of the agonist mAb blocks the induction of transplant tolerance by co stimulation blockade, favors polarization of the allograft response into a TH""""""""!/ Tn17 pattern while inhibiting expansion/function of TregS. In contrast, infusion of an antagonist type anti-Tim-1 mAb (RMT 1-10) aids tolerance induction and polarizes the allograft response into a TH2/ Treg dominant mode. Using these novel tools we propose to explore the role of Tim family of molecules in the regulation of transplantation tolerance. Specifically, we hypothesize that the (i) Tim-3-togalectin- 9 interaction gates the cytopathic alloreactive TH1, Tc1 as well as the newly recognized TH17 compartments and reciprocally regulates the donor reactive TREc compartment, and (ii) Tim-1 -to-Tim-4 interaction regulates the intensity and direction of CD4+ T cell activation.
The specific aims are to analyze: 1) the Tim-3-galectin 9 axis in the allograft response;2) the Tim1-Tim-4 axis in the allograft response;and 3) T cell signaling pathways in the context of Tim-1 and Tim-3 engagement. These studies will provide a functional and mechanistic understanding of how Tim-1 and Tim-3 molecules upon interaction with their ligand regulate immune responses to allotransplants.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI073748-03
Application #
8113322
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
3
Fiscal Year
2010
Total Cost
$228,622
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Meyer Zu Horste, Gerd; Przybylski, Dariusz; Schramm, Markus A et al. (2018) Fas Promotes T Helper 17 Cell Differentiation and Inhibits T Helper 1 Cell Development by Binding and Sequestering Transcription Factor STAT1. Immunity 48:556-569.e7
Iyer, Shankar S; Gensollen, Thomas; Gandhi, Amit et al. (2018) Dietary and Microbial Oxazoles Induce Intestinal Inflammation by Modulating Aryl Hydrocarbon Receptor Responses. Cell 173:1123-1134.e11
Chihara, Norio; Madi, Asaf; Kondo, Takaaki et al. (2018) Induction and transcriptional regulation of the co-inhibitory gene module in T cells. Nature 558:454-459
Dixon, Karen O; Schorer, Michelle; Nevin, James et al. (2018) Functional Anti-TIGIT Antibodies Regulate Development of Autoimmunity and Antitumor Immunity. J Immunol 200:3000-3007
Wu, Chuan; Chen, Zuojia; Xiao, Sheng et al. (2018) SGK1 Governs the Reciprocal Development of Th17 and Regulatory T Cells. Cell Rep 22:653-665
Sabatos-Peyton, Catherine A; Nevin, James; Brock, Ansgar et al. (2018) Blockade of Tim-3 binding to phosphatidylserine and CEACAM1 is a shared feature of anti-Tim-3 antibodies that have functional efficacy. Oncoimmunology 7:e1385690
Dougall, William C; Kurtulus, Sema; Smyth, Mark J et al. (2017) TIGIT and CD96: new checkpoint receptor targets for cancer immunotherapy. Immunol Rev 276:112-120
Boggiano, Cesar; Eichelberg, Katrin; Ramachandra, Lakshmi et al. (2017) ""The Impact of Mycobacterium tuberculosis Immune Evasion on Protective Immunity: Implications for TB Vaccine Design"" - Meeting report. Vaccine 35:3433-3440
Carpenter, Stephen M; Yang, Jason D; Lee, Jinhee et al. (2017) Vaccine-elicited memory CD4+ T cell expansion is impaired in the lungs during tuberculosis. PLoS Pathog 13:e1006704
Wang, Chao; Singer, Meromit; Anderson, Ana C (2017) Molecular Dissection of CD8+ T-Cell Dysfunction. Trends Immunol 38:567-576

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