Follicular T Cells from smB− Common Variable Immunodeficiency Patients Are Skewed Toward a Th1 Phenotype

Abstract

Germinal center follicular T helper (GCTfh) cells are essential players in the differentiation of B cells. Circulating follicular T helper (cTfh) cells share phenotypic and functional properties with GCTfh cells. Distinct subpopulations of cTfh with different helper capabilities toward B cells can be identified: cTfh1 (CXCR3+CCR6−), cTfh2 (CXCR3−CCR6−), and cTfh17 (CXCR3−CCR6+). Alterations in cTfh function and/or distribution have been associated with autoimmunity, infectious diseases, and more recently, with several monogenic immunodeficiencies. Common variable immunodeficiency (CVID) disease is the commonest symptomatic primary immunodeficiency with a genetic cause identified in only 2–10% of patients. Although a heterogeneous disease, most patients show a characteristic defective B cell differentiation into memory B cells or antibody-secreting cells. We investigated if alterations in CVID cTfh cells frequency or distribution into cTfh1, cTfh2, and cTfh17 subpopulations and regulatory follicular T (Tfr) cells could be related to defects in CVID B cells. We found increased percentages of cTfh exhibiting higher programmed death-1 expression and altered subpopulations distribution in smB− CVID patients. In contrast to smB+ patients and controls, cTfh from smB− CVID patients show increased cTfh1 and decreased cTfh17 subpopulation percentages and increased CXCR3+CCR6+ cTfh, a population analogous to the recently described pathogenic Th17.1. Moreover, Tfr cells are remarkably decreased only in smB− CVID patients. In conclusion, increased cTfh17.1 and cTfh1/cTfh17 ratio in CVID patients could influence B cell fate in smB− CVID patients, with a more compromised B cell compartment, and the decrease in Tfr cells may lead to high risk of autoimmune conditions in CVID patients.

Functions of Tfh Cells in Common Variable Immunodeficiency

“…As explained earlier, TFH can be divided into two subsets: the non-efficient helper TFH1 and the efficient helpers TFH2 and TFH17. Interestingly, we (75) and others (77,78,80) highlight a specific increase of the circulating TFH1 only in non-infectious CVID patients. Moreover, CXCR3 + (75) or Tbet + (78) cells were amplified in secondary lymphoid organs of CVID patients, suggesting that the blood observations reflect the GC counterpart.…”

“…Interestingly, our group (75) and others (76)(77)(78) observed an increase of circulating TFH (memory CXCR5 + CD4 T cells) in CVID patients harboring non-infectious complications. Moreover, TFH expressing PD-1 were present at higher levels in CVID patients with complications (75)(76)(77)(78). Patients classified as smB − based on the EUROClass have <2% of switched memory B cells among circulating CD19 + cells (12).…”

“…Patients classified as smB − based on the EUROClass have <2% of switched memory B cells among circulating CD19 + cells (12). Interestingly, smB − patients have higher levels of circulating TFH (77) [which is even more pronounced in the smB − CD21 low subgroup (78)] than smB + patients. The switched memory B cell population (IgG + ) contains some autoreactive B cells in normal adults (79), and CD21 low memory B cells are increased in several autoimmune contexts (18).…”

Follicular regulatory T cells: a novel target for immunotherapy?

“…Altered frequencies and/or the suppressive capacity of cTfr cells have been elucidated in a multitude of AIDs, including systemic AIDs and organ‐specific AIDs (shown in Table ). Systemic AIDs involve rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), ankylosing spondylitis (AS), IgG4‐related disease (IgG4‐RD) and common variable immune deficiency (CVID) . Organ‐specific AIDs involve multiple sclerosis (MS), myasthenia gravis (MG), Hashimoto's thyroiditis (HT), primary biliary cholangitis (PBC), type 1 diabetes (T1D) and ulcerative colitis (UC) .…”

“…Systemic AIDs involve rheumatoid arthritis (RA), [58][59][60][61][62] systemic lupus erythematosus (SLE), 33,63-65 Sj€ ogren's syndrome (SS), 14,66,67 ankylosing spondylitis (AS), 68 IgG4related disease (IgG4-RD) 69 and common variable immune deficiency (CVID). 70 Organ-specific AIDs involve multiple sclerosis (MS), 15,71,72 myasthenia gravis (MG), [73][74][75] Hashimoto's thyroiditis (HT), 76 primary biliary cholangitis (PBC), 77 type 1 diabetes (T1D) 78 and ulcerative colitis (UC). 79 It is also demonstrated that when the regulatory capacity of Tfr cells is impaired, the expansion of Tfr cells is accompanied by the development of autoimmunity in mice.…”