MS is an autoimmune disease potentially mediated by activated myelin reactive Th1/Th17 T cells in agenetically susceptible host. Kuchroo recently discovered that Th1 cells selectively express TIM-3, and itsligation regulates tolerance induction. New, complementary data sets generated in the Hafler & Kuchroolabs demonstrate that TIM-3 is also expressed on APCs, including both dendritic cells and monocytes.Contrary to the consequences of TIM-3 engagement on T cells, ligation of TIM-3 on APCs may promoteTh1-mediated immunity in that stimulation of monocytes with the TIM-3 ligand galectin-9 (Gal-9) inducesTNF-a and IL-6 secretion. Moreover, we have demonstrated that microglia in CNS white matter expresshigh levels of TIM-3, and glial expression of TIM-3 and Gal-9 are up-regulated in MS lesions. This leads usto hypothesize that the altered expression or function of TIM-3 by T cells and circulating APCs andCNS microglia may alter the balance of Th1 differentiation, and perhaps is associated with chronic CNSinflammation due to up-regulation of Gal-9 expression on astrocytes, inducing the activation of TIM-3*microglia. Thus, it is possible that the innate TIM-3/Gal-9 pathway may be involved with transition tosecondary progressive disease in patients with MS. Experiments in Aim 1 have been designed to provide uswith a detailed mechanistic understanding of how TIM-3 expression on APCs modulates their activity, andhow this may subsequently influence the balance of effector versus regulatory T cell differentiation.
In Aim1 b, based on our discovery of the presence of TIM-3 on CD11b+ microglia in white matter of normal brain,and the coordinated modulation of TIM-3 & Gal-9 expression depending on the nature of CNS inflammation,we will determine how this pathway modulates glial responses within the CNS. In collaboration withKuchroo, we propose experiments to examine the kinetics of TIM-3 induction on microglia associated withmigration of hematopoietic cells into the CNS.
Aim 2 will investigate our recent discovery that 5 distinct TIM-3 splice variants exist in humans, including membrane & soluble forms with variable potential signalingcapacity. Using quantitative RT-PCR analysis in conjunction with techniques to modulate specific TIM-3isoforms, we will explore how relative differences in the expression of these TIM-3 isoforms may influence Tcell vs. APC biology.
Our third aim will extend our analysis of TIM-3 regulation of APC function by definingthe TIM-3 signaling pathways in T cell vs. monocyte lineage cells. We will perform structure/functionexperiments to determine which structural elements in the cytoplasmic tail of TIM-3 are responsible for itseffects on cytokine production and downstream signaling pathways in TIM-3+ T cells and monocytic cells,and will determine which cytoplasmic signaling proteins are recruited to the cytoplasmic tail of TIM-3 tomediate activation of downstream signaling pathways. These experiments will determine how differences inTIM-3 isoform expression and signaling dictate divergent functional outcomes in adaptive versus innateimmunity and how this innate pathway may be involved in the pathoaenesis of autoimmune disease.
|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|
|Das, Madhumita; Zhu, Chen; Kuchroo, Vijay K (2017) Tim-3 and its role in regulating anti-tumor immunity. Immunol Rev 276:97-111|
|Lucca, Liliana E; Hafler, David A (2017) Co-inhibitory blockade while preserving tolerance: checkpoint inhibitors for glioblastoma. Immunol Rev 276:9-25|
|Wu, Chuan; Chen, Zuojia; Dardalhon, Valerie et al. (2017) The transcription factor musculin promotes the unidirectional development of peripheral Treg cells by suppressing the TH2 transcriptional program. Nat Immunol 18:344-353|
|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|
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