Follicular Helper CD4+ T Cells, Follicular Regulatory CD4+ T Cells, and Inducible Costimulator and Their Roles in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

Abstract

Follicular helper CD4+ T (TFH) cells are a specialized subset of effector T cells that play a central role in orchestrating adaptive immunity. TFH cells mainly promote germinal center (GC) formation, provide help to B cells for immunoglobulin affinity maturation and class-switch recombination of B cells, and facilitate production of long-lived plasma cells and memory B cells. TFH cells express the nuclear transcriptional repressor B cell lymphoma 6 (Bcl-6), the chemokine (C-X-C motif) receptor 5 (CXCR5), the CD28 family members programmed cell death protein-1 (PD-1) and inducible costimulator (ICOS) and are also responsible for the secretion of interleukin-21 (IL-21) and IL-4. Follicular regulatory CD4+ T (TFR) cells, as a regulatory counterpart of TFH cells, participate in the regulation of GC reactions. TFR cells not only express markers of TFH cells but also express markers of regulatory T (Treg) cells containing FOXP3, glucocorticoid-induced tumor necrosis factor receptor (GITR), cytotoxic T lymphocyte antigen 4 (CTLA-4), and IL-10, hence owing to the dual characteristic of TFH cells and Treg cells. ICOS, expressed on activated CD4+ effector T cells, participates in T cell activation, differentiation, and effector process. The expression of ICOS is highest on TFH and TFR cells, indicating it as a key regulator of humoral immunity. Multiple sclerosis (MS) is a severe autoimmune disease that affects the central nervous system and results in disability, mediated by autoreactive T cells with evolving evidence of a remarkable contribution from humoral responses. This review summarizes recent advances regarding TFH cells, TFR cells, and ICOS, as well as their functional characteristics in relation to MS.

Increased Intrathecal Activity of Follicular Helper T Cells in Patients With Relapsing-Remitting Multiple Sclerosis

“…In this study, we investigated the involvement of Tfh cells in MS. Several studies have reported dysregulated levels of Tfh and Tfr cells in blood from patients with MS suggesting their importance in disease pathogenesis. 6 , 17 , 27 However, there are discrepancies between studies reporting both elevated and similar frequencies of circulating Tfh cells in patients with RRMS compared with healthy controls. 10 , 14 , 15 , 28 This may at least partially relate to differing definitions of Tfh cells.…”

“…Follicular helper T (Tfh) cells are a subset of peripheral lymphoid tissue T cells primarily located in germinal centers where they function to promote B-cell differentiation to antibody-producing plasma cells. 4 - 6 Conversely, follicular regulatory T cells (Tfr) function by suppressing the Tfh-induced B-cell response. 7 Phenotypically, both Tfh and Tfr cells express CD4 and the lymphoid follicle-homing chemokine receptor CXCR5, and their expression of programmed cell death protein 1 (PD-1) is induced by cognate antigen activation.…”

Low absolute CD4+ T cell counts in peripheral blood: an independent predictor of inferior survival in natural killer/T-cell lymphoma—a retrospective cohort study

“…The ACD4C has also been considered a key factor in predicting responses to chemotherapy and survival in patients with DLBCL, FL, and MCL. A low level of blood CD4 + T cells was shown to be correlated with inferior survival in DLBCL and FL, but had a negative prognostic effect in MCL, due to the heterogeneity of MCL (13)(14)(15). A study has reported the prognostic role of ACD4C in ENKTL in the past (16), but this study deserves further exploration due to the small number of cases (only 70 patients).…”

“…CD4 + T cells play a crucial role in inducing immune responses against tumors and influencing lymphoma outcomes. Clinical studies have reported that enhanced levels of blood CD4 + T cells are related to a better prognosis for various types of NHL, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL) (12)(13)(14)(15).…”

B cell depletion attenuates CD27 signaling of T helper cells in multiple sclerosis

“…Given the central role of Tfh cells in providing costimulatory maturation and proliferation signals to B cells, their decrease in frequency after depletion of B cells highlights the importance of direct cell-cell interactions during the immunopathology of MS. Numerous studies underscore the importance of Tfh cells in MS pathophysiology (36, 37, 70) . CXCL13, a chemokine involved in the migration of B cells and Tfh cells (71, 72) , is found to be elevated in the CSF of MS patients (73) and predictive of a more severe disease course (74) .…”