CD4 + T helper (Th) cells play central roles in immunity in health and disease. While much is known about the effector function of Th cells in combating pathogens and promoting autoimmune diseases, the roles and biology of memory CD4 + Th cells are complex and less well understood. In human autoimmune diseases such as multiple sclerosis (MS), there is a critical need to better understand the function and biology of memory T cells. In this review article we summarize current concepts in the field of CD4 + T cell memory, including natural history, developmental pathways, subsets, and functions. Furthermore, we discuss advancements in the field of the newly-described CD4 + tissue-resident memory T cells and of CD4 + memory T cells in autoimmune diseases, two major areas of important unresolved questions in need of answering to advance new vaccine design and development of novel treatments for CD4 + T cell-mediated autoimmune diseases.

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Multiple sclerosis (MS) is a T cell-driven autoimmune disease. There are many unknowns regarding the disease etiology and pathogenesis. Importantly, the mechanisms of peripheral tolerance and dysregulation of pathogenic mechanisms are poorly understood. It is known that patients with MS exhibit myelin reactive T cells in the blood; however healthy controls also show myelin reactive T cells in the blood. Additionally, T cells from patients with MS react to many different myelin peptides. Current human studies do not support that patients exhibit large populations of T cells specific for a single myelin-antigen responsible for the induction of autoimmune pathology. In contrast, a quorum of several low avidity autoreactive T cells specific for one epitope might suffice to induce autoimmunity. We hypothesized that a quorum could be established and induce autoimmunity by small numbers of antigen-specific T cells recognizing different myelin antigen peptides. We found that disease in the experimental autoimmune encephalomyelitis (EAE) model of MS can be initiated by the cooperation of small numbers of myelin peptide-specific T cells reactive against different myelin epitopes. These results support the hypothesis that a quorum of autoreactive T cells could suffice to initiate autoimmune disease. We have developed a system whereby T cells of different antigen specificities can be traced in order to track the dynamics and kinetics of those T cells in disease initiation and progression. The results of this study provide further insights into the dynamic interactions between T cells of different antigen specificities.