Decreased dependence of myelin basic protein-reactive T cells on CD28-mediated costimulation in multiple sclerosis patients. A marker of activated/memory T cells.

Abstract

Although multiple sclerosis (MS) patients and healthy individuals have similar frequencies of myelin basic protein (MBP)-specific T cells, the activation state of these cells has not been well characterized. Therefore, we investigated the dependence of MBP-reactive T cells on CD28-mediated costimulation in MS patients, healthy controls, and stroke patients. MBP-reactive T cells from healthy controls and stroke patients failed to proliferate efficiently when costimulation was blocked using anti-CD28, consistent with a naive T cell response. In contrast, MBP-specific T cell proliferation was not inhibited, or was only partially inhibited when CD28-mediated costimulation was blocked in MS patients. Blockade of CD28 failed to inhibit tetanus toxoid-specific T cell proliferation in both the controls and MS patients, demonstrating that memory cells are not dependent on CD28-mediated costimulation. Limiting dilution analysis indicated that the frequency of MBP-reactive T cells was significantly decreased in healthy controls compared with MS patients when CD28-mediated costimulation was blocked. These data suggest that MBP-reactive T cells are more likely to have been activated in vivo and/or differentiated into memory T cells in MS patients compared with controls, indicating that these cells may be participating in the pathogenesis of MS.

The voltage-gated potassium channel Kv1.3 is highly expressed on inflammatory infiltrates in multiple sclerosis brain

“…In contrast, myelin-reactive T cells from the PB of healthy controls are Kv1.3 low , consistent with a naive͞T CM phenotype (11). Our results corroborate reports by other investigators who have found a preponderance of chronically activated memory cells in the myelinreactive pool in MS patients (18,19). Here, we provide definitive evidence that Kv1.3 ϩ is highly expressed in the perivenular and parenchymal inflammatory infiltrates of MS brain tissue and on T cells from the cerebrospinal fluid (CSF).…”

Allelic variant inCTLA4alters T cell phosphorylation patterns

“…The CT60 allele may affect the memory T cell subset because these cells may be subject to greater regulation by CTLA-4 (30) and thus potentially their isoforms. Moreover, although autoreactive T cells are present in healthy subjects and those with autoimmune disease, those circulating in individuals with autoimmune disease are in an activated/memory state (31)(32)(33). However, it is tempting to speculate that the CT60 allelic variant in the CTLA4 region lowers the threshold of activation by naive, CD4 ϩ CD45RA high T cells, allowing self-antigen reactive T cells to enter into an activated state directly leading to autoimmune disease.…”

Modulating Co-Stimulation

“…It has also been demonstrated that in patients with MS, myelin basic protein reactive T cells are less dependent on CD28 co-stimulation indicating a different state of activation of potentially pathogenic T cells. 101 The dependency on CD28 co-stimulation is also related to the strength of the signal delivered to the cells. T-cell activation induced by weak agonists or antigens provided at low concentration is dependent on co-stimulation.…”

“…The different requirement for B7 co-stimulation suggests that memory cells that are chronically exposed to CNS auto-antigens are in a different state of activation compared to cells from healthy individuals. 101 A phase I, dose-escalation study to evaluate the safety and tolerability of CTLA-4Ig in patients with relapsingremitting MS was completed at the Partners Multiple Sclerosis Center (Boston, MA). We evaluated the disease-specific safety of a single infusion of CTLA-4 Ig in patients with relapsing-remitting MS, as well as the effects on immune functions of these patients.…”