Table 2.

Immune alterations present in ME/CFS and changes evident in B cells, T cells, and NK cells (99, 253–255, 278, 445–482).

Cell type	Abnormalities	Comments
B cells	Increase in B cells (445), including CD21+, CD19+, and CD5+ B cells (446, 447), and antigen-driven clonal B cell expansion (448).	CD19/CD21 complex: Promotes BCR signalling in response to complement-tagged antigens (449). CD5+ B cells: Likely involved in antigen presentation, tolerance induction, the idiotype network, and autoantibody production (450).
Cytotoxic T lymphocytes (CD8)	Increase in activated CD8+ T cells (451–453) expressing activation markers HLA-DR (446, 451, 452, 454), CD26 (446), and CD38+ (451, 452, 454). A reduction in CD11b levels was observed (454). Some papers have illustrated a reduced response of T cells to mitogens and antigens (253–255). Also found decreased CD8 suppressor cell population (452).	CD38: T cell surface protein that contributes to cell activation (455, 456). HLA-DR: A marker of T cell activation (457, 458) that is also increased in autoimmune diseases (459).
	Decreased cytotoxicity of CD8+ T cells (253, 460, 461, 483).	It is possible that these changes reflect T-cell exhaustion in prolonged disease duration (462).
	At rest and upon activation, the CD8+ T cells had a reduced mitochondrial membrane potential (254). Additionally, one subset of CD8+ cells had an elevated mitochondrial mass (254).	Reduced mitochondrial membrane potential: This phenotype may be indicative of T cell exhaustion and is typically observed in chronic viral infection (463). Increased mitochondrial mass: Suggests impaired mitochondrial and glycolytic metabolism in ME/CFS T cell subsets (464).
Regulatory T cells (Tregs)	Increased Treg cells in ME/CFS patients (278, 465–467). However, some studies did not take the stages of the illness into consideration [much as in ostensibly conflicting accounts of acute COVID-19 (468)], nor were they sufficiently powered to stratify subtypes. As a result, there is inconclusive literature around whether Tregs are increased or decreased in ME/CFS (451, 467).	Tregs work to suppress the immune system by inhibiting T cell proliferation and cytokine production, while also preventing autoimmunity (469). Hence, an increase in Tregs may show disruption of the immune system since this subpopulation functions to suppress the immune response.
T-follicular helper cells (CD4)	The resting glycolysis of the ME/CFS CD4+ T cells at rest was found to be significantly lower than cells from healthy controls (254).	In cases of short-term, rapid fuel production, remodelling of CD4+ T cells is possible to elevate glycolysis and optimise oxidative phosphorylation (464).
Natural killer (NK) cells	NK cell functioning is reduced in ME/CFS patients (470–473). Conversely, an elevation in CD16+/CD3- NK cells has been found in some ME/CFS patients (452).	NK cells form part of the innate immune system and control various microbial infections by preventing their spread and subsequent tissue damage (475). Hence, this beneficial functioning is reduced in ME/CFS.
	Reduction in NK cytotoxicity (446, 451, 476, 477). Conversely, some studies have not found a decreased cytotoxic activity of NK cells (99, 478–482).

BCR, B cell receptor; CD4, T-follicular helper cell; CD8, cytotoxic T lymphocyte; HLA, human leukocyte antigen; ME/CFS, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; NK, natural killer cell; Treg, regulatory T cell.