TABLE 1.

Key studies of human cTFH responses following SARS‐CoV‐2 infection and vaccination

Cohort	Detection method	Dominant phenotype/cytokine profile of cTFH cells	Key cTFH findings	Reference
Acute and convalescent cohorts
Acute and convalescent COVID‐19	Bulk ICOS+PD‐1+ cTFH cells	Activation of CXCR3+CCR6−cTFH cells	CXCR3+ cTFH cells positively correlated with neutralizing antibody titers	60
Acute and convalescent COVID‐19	Antigen‐specific cTFH cells by AIM	Greater frequency of CXCR3+CCR6− than CXCR3−CCR6+ S‐specific cTFH cells in acute samples Greater frequency of CXCR3−CCR6+ than CXCR3+CCR6− S‐specific cTFH cells in convalescent samples IFNγ producing cTFH cells IL‐17A assessed but not detected	Spike‐specific cTFH cells detected in acute and convalescent COVID‐19 individuals Spike‐specific CXCR3−CCR6+ cTFH cells correlated with lower disease severity	65
Acute and convalescent COVID‐19	Bulk ICOS+PD‐1+ cTFH cells	CXCR3+ cTFH cells	ICOS+PD‐1+ CXCR3+ cTFH cells increased acute mild and severe COVID‐19 compared to healthy controls ICOS+PD‐1+ CXCR3− cTFH cells modestly increased in severe COVID‐19 compared with healthy controls ICOS+PD‐1+ CXCR3+ and CXCR3− cTFH cells positively correlated with ASC frequencies and CXCL13 levels in plasma	64
Convalescent cohorts
Convalescent COVID‐19	Antigen‐specific cTFH cells by AIM	Not reported	Spike‐, membrane protein‐, and nucleocapsid‐specific cTFH cells detected Spike‐, membrane protein‐, and nucleocapsid‐specific cTFH cells positively correlated with neutralizing antibodies and N‐specific IgG antibodies	69
Convalescent COVID‐19 (up to 8 months)	Antigen‐specific cTFH cells by AIM	Increase in CCR6+ spike‐specific cTFH cells over time	Spike‐ and membrane‐specific cTFH cells persist up to at least 6 months postsymptom onset Reduction in frequency of PD‐1hi spike‐specific cTFH cells over time	23
Convalescent COVID‐19	Bulk cTFH cells	CXCR3+ or CXCR3−	CCR7loPD‐1+ cTFH cells increased in convalescent COVID19 individuals compared with healthy controls Frequency of CXCR3+, but not CXCR3−, cTFH cells positively correlated with IgG, IgM and IgA SARS‐CoV‐2‐specific antibodies	63
Convalescent COVID‐19	Antigen‐specific cTFH cells by AIM	CXCR3+ or CXCR3−	Spike‐specific cTFH cells detected in convalescent individuals Spike‐specific cTFH cells in convalescent were mostly CXCR3−CCR6+ CXCR3−CCR6+ spike‐specific cTFH cells negatively correlated with neutralizing antibodies, while CXCR3+CCR6− spike‐specific cTFH cells positively correlated with neutralizing antibodies	66
Convalescent COVID‐19	Antigen‐specific cTFH cells by AIM	IFNγ producing cTFH cells	Spike‐specific cTFH cells detected in convalescent individuals Spike‐specific cTFH cells persist up to at least 3 months postsymptom onset	67
Convalescent COVID‐19	Antigen‐specific cTFH cells by AIM	Spike‐specific cTFH 1 and cTFH 2 Membrane‐specific cTFH 1 and cTFH 1/17 Nucleocapsid‐specific cTFH 1	Spike‐, membrane protein‐ and nucleocapsid‐specific cTFH cells detected Spike‐specific CD4+ T cells more polarized toward cTFH than Th1, while nucleocapsid‐specific CD4+ T cells more polarized toward Th1 than cTFH	68
Convalescent COVID‐19 (up to 150 days)	Antigen‐specific cTFH cells by AIM	Not reported	Spike‐specific cTFH cells detected in convalescent individuals Decay of spike‐specific cTFH cells, with a t1/2 of 128 days	24
Convalescent COVID‐19	Bulk PD‐1+CXCR5+ cTFH cells & antigen‐specific cTFH cells by AIM	CXCR3+ or CXCR3− IFNγ and IL‐21 producing cTFH cells other cytokines not reported	CXCR3+ cTFH cells positively correlated with neutralizing antibody titers CXCR3− cTFH cells negatively correlated with neutralizing antibody titers	62
Vaccination cohorts
Healthy and MS patients on a‐CD20 therapy receiving 2 doses of mRNA vaccine	Antigen‐specific cTFH cells by AIM	CXCR3+	Poor maintenance of cTFH cells postvaccination in MS‐aCD20 patients Spike‐specific cTFH cells positively correlated with spike‐specific IgG and memory B cell responses to vaccination	75
Naïve and COVID‐19 recovered individuals receiving 2 doses of BNT162b or mRNA‐1273 vaccine	Antigen‐specific cTFH cells by AIM	Not reported	Vaccination induced spike‐specific cTFH cells in both groups Pre‐vaccination spike‐specific cTFH frequencies in recovered individuals, positively corelated with postvaccination neutralizing antibodies to D164G and B.1.351 (beta) variant	76
Naïve and COVID‐19 recovered individuals receiving 1 dose of BNT162b vaccine	Antigen‐specific cTFH cells by AIM	IFNγ producing cTFH cells IL‐17A assessed but not detected	Vaccination induced spike‐specific cTFH cells in both groups Previously infected individuals had higher frequencies of spike‐specific cTFH cells at ∼3 weeks postvaccination (1 dose) Pre‐vaccination spike‐specific cTFH frequencies in recovered individuals, positively corelated with postvaccination IgG and IgA, but not IgM, antibodies to spike	78
Naïve and COVID‐19 recovered individuals receiving 2 doses of BNT162b or mRNA‐1273 vaccine	Antigen‐specific cTFH cells by AIM	Not reported	Vaccination induced spike‐specific cTFH cells in both groups Spike‐specific cTFH cells peak at ∼1 month and then wane, contrary to spike‐specific TH1 cells that are stable for at least 6 months Spike‐specific cTFH cells at 2 weeks postvaccination in naive individuals correlates with postvaccination neutralization titers and spike‐specific MBCs	77