Abstract

Cytotoxic CD4+ T cells (CD4 CTL) are terminally differentiated T helper cells that contribute to autoimmune diseases, such as multiple sclerosis. We developed a novel triple co-culture transwell assay to study mutual interactions between CD4 CTL, conventional TH cells, and regulatory T cells (Tregs) simultaneously. We show that, while CD4 CTL are resistant to suppression by Tregs in vitro, the conditioned medium of CD4 CTL accentuates the suppressive phenotype of Tregs by upregulating IL-10, Granzyme B, CTLA-4, and PD-1. We demonstrate that CD4 CTL conditioned medium skews memory TH cells to a TH17 phenotype, suggesting that the CD4 CTL induce bystander polarization. In our triple co-culture assay, the CD4 CTL secretome promotes the proliferation of TH cells, even in the presence of Tregs. However, when cell−cell contact is established between CD4 CTL and TH cells, the proliferation of TH cells is no longer increased and Treg-mediated suppression is restored. Taken together, our results suggest that when TH cells acquire cytotoxic properties, these Treg-resistant CD4 CTL affect the proliferation and phenotype of conventional TH cells in their vicinity. By creating such a pro-inflammatory microenvironment, CD4 CTL may favor their own persistence and expansion, and that of other potentially pathogenic TH cells, thereby contributing to pathogenic responses in autoimmune disorders.

Highlights

  • Cytotoxic CD4+ T cells (CD4 CTL) arise during the chronic activation of the immune system

  • We previously found that expansion of this T cell subset correlates with disability in experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis, a demyelinating autoimmune disease of the central nervous system [14]

  • Treg suppression assays were performed with T helper (TH) cells or CD4 CTL as responders

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Summary

Introduction

Cytotoxic CD4+ T cells (CD4 CTL) arise during the chronic activation of the immune system. CD4 CTL are co-stimulation independent, resistant to apoptosis, and less susceptible to suppression by regulatory T cells (Tregs) [4,6,7,8,9]. They are suspected of contributing to many inflammatory diseases, due to their cytotoxic capabilities via the expression of natural killer cell receptors and the production of perforin and granzymes, their ability to infiltrate target tissues, such as the central nervous system, using the fractalkine receptor.

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