Strategies designed to specifically suppress the function of myelin-reactive T cells are an objective of pharmacological therapy in multiple sclerosis (MS). We have focused our studies on identifying markers of costimulation independent memory cells that might be amenable to therapeutic intervention. In the last two years, we have demonstrated that two chemokine receptors, CXCR3 and CXCR6, are highly expressed on Th1 myelin specific effector T cells. We have also determined that the loss of the lymph node homing chemokine receptor, CCR7, is an excellent marker of conversion of myelin reactive T cell lines from an early effector state CD45RA-/CCR7+) to an effector memory state (TEM=CD45RA-/CCR7-), and that these TEM are synonymous with the previously described costimulation independent T cells in MS. In a recent collaboration, we have now identified a voltage-gated potassium (K+) channel, Kv1.3, which is specifically and highly expressed on chronically differentiated TEM. We have demonstrated that the myelin reactive Kv1.3highTEM are present in MS patients and not in controls. We will now characterize the specificity of Kv1.3 expression on effector and regulatory subtypes of CD4 and CD8 T cells, and test the hypothesis that specific Kv1.3 inhibitors will selectively suppress TEM, without compromising immediate immune responses or regulatory T cells. We will examine these hypotheses through the following specific aims:
Specific Aim 1. To determine the peptide specificity of the myelin reactive TEM (CCR7-, Kv1.3highlKCa1low).
Specific Aim 2. To determine whether CD8 myelin specific T cells from MS patients have the TEM (CCR7-, Kv1.3highlKCa1 low) phenotype as compared to controls using class I tetramers.
Specific Aim 3. To evaluate the effects of Kv1.3 antagonists on TEM function.
Specific Aim 4. To determine the expression and function of Kv1.3 on myeloid lineage cells in vitro and in the inflammatory infiltrate of MS brain tissue. The results from these K+ channel studies on human immune cells will have broad implications for defining the potential role of K+ channel blockers in specifically targeting effector cells, and could lead to novel treatment strategies for MS.
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