Regulation of the T Cell Response
Laboratory of Autoimmunity
Vipin Kumar, M.S., Ph.D.
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Regulation of the T Cell Response
Dr. Kumar and his research team focus on a number issues related to the mechanisms involved in regulation of the T cell response. He has been investigating an important negative feedback regulatory mechanism based upon the recognition of TCR-peptide/MHC complexes by CD4 and CD8 regulatory T cells (Treg) in a model of human multiple sclerosis. His group's effort over the past 15 years has defined a number of cellular players and their network interactions at the molecular level. He has found that CD4 Treg recognize a TCR peptide of pathogenic CD4 T cells in a class II MHC context, which then induce the recruitment of CD8 Treg, the ultimate effectors of regulation, that specifically kill the target pathogenic CD4 T cells. The CD8 Treg population has a unique phenotype in that they are CD8aa+ and recognize a different TCR peptide in the context of a non-classical class Ia molecule, Qa-1.
These studies represent the most comprehensive characterization of regulatory T cells as to their antigen specificity, MHC-restriction, TCR repertoire, as well as their mechanism of regulation at the clonal level. The laboratory is investigating the roles of these Treg populations in several diseases, including multiple sclerosis, diabetes, arthritis, and cancer to determine whether they could be potential targets for therapeutic intervention. Are CD4 and CD8 Treg primed by the pathways of cross-presentation of TCR peptides by dendritic cells following the capture of apoptotic pathogenic T cells?
Dr. Kumar's team also has discovered a self-glycolipid ligand, sulfatide that binds to the CD1d molecule and is recognized by a distinct population within the non-conventional CD1d-restricted NK T cell subset. These NK T cells are different from the invariant a-GalCer-reactive Va14+ NK T cells. They have found that sulfatide-reactive NK T cells are enriched in the target organ (CNS) during autoimmune demyelination. They are currently investigating the interaction of these T cells with the local antigen-presenting cells in the CNS, for example microglia.
Several important issues are being addressed: what are the molecular features of the recognition of sulfatide by the CD1d and TCR; how and in which compartment is sulfatide processed and presented by CD1d molecules; is the pathway of presentation of sulfatide similar to or distinct from that of presentation of the foreign lipid, a-GalCer; is there an interaction between sulfatide-reactive and the invariant Va14+ NK T cells, and if so what are the consequences of this interaction in vivo; why do these cells normally reside in the liver? The objective of these studies is to investigate whether sulfatide-reactive T cells can be targeted to prevent and treat autoimmune diseases, including multiple sclerosis, diabetes, lupus, hepatitis as well as Alzhiemer's.