Follicular Helper CD4⁺ T Cells in Human Neuroautoimmune Diseases and Their Animal Models

Table 1

TFH cells and TFH-associated molecules in neuroautoimmune diseases and their animal models.

Neuroautoimmune diseases	Changes of TFH cells and TFH-associated molecules	Relevance to the diseases	References
MS	↑ frequency of circulating CD4^+CXCR5^+ICOS^+ T cells in RRMS and SPMS patients; ↑ gene expression of ICOS, IL-21, and IL-21R in purified CD4^+ T cells in SPMS patients; ↑ ICOS expression in CSF cells in progressive MS patients; ↑ IL-21 expression of CD4^+ T cells in infiltrating active lesions of CNS; ↓ frequency of blood CXCR3^+ Th1-like TFH cells in MS patients; ↑frequency of blood CCR6^+ Th17-like TFH cells in PPMS patients	Positive correlation between circulating CD4^+CXCR5^+ICOS^+ T cells and disease progression in SPMS	[64–66]
EAE	CXCR5 mRNA present in spinal cords; CNS infiltrating CXCR5^+ cells were CD3^+CD4^+ T cells in spinal cord MNCs		[70]
NMO/NMOSD	↑ frequency of circulating CD4^+CXCR5^+PD-1^+ T cells; ↑ serum level of IL-21; ↑ secretion of IL-21 in PBMC cultures; ↑ serum and CSF levels of CXCR5	A correlation between circulating CD4^+CXCR5^+PD-1^+ T cells and disease activity; Positive correlation between the level of IL-21 produced by peripheral blood CD4^+ T cells and EDSS score; Positive correlation between CSF CXCL13 level and disease disability	[83–85]
MG	↑ frequency of circulating CD4^+CXCR5^+ T cells, CD4^+CXCR5^+CD45RO^+ T cells, CD4^+CXCR5^+ PD-1^hi T cells, and CD4^+CXCR5^+ICOS^hi T cells; ↑ serum level of CXCL13; ↑ expression of IL-21 mRNA in PBMCs	Positive correlation between circulating CD4^+CXCR5^+ T cells and disease severity; Positive correlation between circulating CD4^+CXCR5^+ICOS^hi T cells and serum anti-AChR Ab concentration; Positive correlation between circulating CD4^+CXCR5^+PD-1^hi T cells and serum anti-AChR Ab concentration; Positive correlation between serum level of CXCL13 and disease severity; Positive correlation between serum level of CXCL13 or expression of IL-21 mRNA in PBMCs and circulating CD4^+CXCR5^+ICOS^hi T cells	[97–100]
EAMG	↑ frequency of CD4^+CXCR5^+PD-1^+ TFH cells and increased expression of Bcl-6 and IL-21 in spleens	Positive correlation between serum level of anti-AChR Abs and the frequency of TFH cells in spleen	[102]

AChR, acetylcholine receptor; Bcl-6, B cell lymphoma 6; CCR6, CC chemokine receptor 6; CNS, central nervous system; CSF, cerebrospinal fluid; CXCL13, CXC-chemokine ligand 13; CXCR3, CXC-chemokine receptor 3; CXCR5, CXC-chemokine receptor 5; EAE, experimental autoimmune encephalomyelitis; EAMG, experimental autoimmune myasthenia gravis; EDSS, expanded disability status scale; ICOS, inducible costimulator; IL-21, interleukin 21; IL-21R, IL-21 receptor; MG, myasthenia gravis; MNCs, mononuclear cells; MS, multiple sclerosis; NMO, neuromyelitis optica; NMOSD, neuromyelitis optica spectrum disorders; PBMC, peripheral blood mononuclear cell; PD-1, programmed death-1; RRMS, relapsing remitting multiple sclerosis; SPMS, secondary progressive multiple sclerosis.