Production of IgG antibodies to pneumococcal polysaccharides is associated with expansion of ICOS+ circulating memory T follicular-helper cells which is impaired by HIV infection

Abstract

Dysfunction of T follicular-helper (TFH) cells is a possible cause of impaired germinal centre (GC) and IgG antibody responses in individuals with human immunodeficiency virus-1 (HIV-1) infection and might contribute to decreased magnitude and isotype diversification of IgG antibodies to pneumococcal polysaccharides (PcPs). We examined the production of IgG1 and IgG2 antibodies to PcPs 4, 6B, 9V and 14 by enumerating antibody secreting cells (ASCs) at day (D) 7 and determining fold-increase in serum antibody levels at D28 after vaccination with unconjugated PcPs in HIV seronegative subjects (n = 20) and in HIV patients who were receiving antiretroviral therapy (ART) (n = 28) or who were ART-naive (n = 11) and determined their association with ICOS+ and ICOS- circulating memory TFH (cmTFH) cells (CD4+CD45RA-CD27+CXCR5+PD-1+) and short lived plasmablasts (SPBs) at D7, and with PcP-specific and total IgM+ and IgG+ memory B cells at D0. In HIV seronegative subjects, production of IgG1+ and IgG2+ ASCs was consistently associated with the frequency of ICOS+ cmTFH cells but not ICOS- cmTFH cells or memory B cells. In contrast, post-vaccination ASCs in HIV patients, regardless of ART status, were lower than in HIV seronegative subjects and not associated with ICOS+ cmTFH cells, the expansion of which was absent (ART-naive patients) or much lower than in HIV seronegative subjects (ART-treated patients). Production of SPBs was also lower in ART-naive patients. Fold-increase in IgG2 antibodies at D28 also correlated with ICOS+ cmTFH cells at D7 in HIV seronegative subjects but not in HIV patients. These novel findings provide evidence that ICOS+ cmTFH cells contribute to the regulation of PcP-specific IgG antibody responses, including isotype diversification, and that TFH cell dysfunction may be a cause of impaired PcP-specific IgG antibody responses and increased susceptibility to pneumococcal disease in HIV patients.

Pregnancy favors circulating IL‐21–secreting TFH‐like cell recovery in ARV‐treated HIV‐1–infected women

“…17,18 In untreated HIV-1-infected patients, an increase in T FH cells in the lymph nodes has been associated with both viraemia and hypergammaglobulinaemia. [20][21][22] By contrast, in a small fraction of patients who spontaneously controlled HIV-1 replication, the maintenance of a high frequency of functional cT FH cells able to induce broadly neutralizing antibodies (bNabs) against different HIV-1 strains is critical to avoid disease progression. [20][21][22] By contrast, in a small fraction of patients who spontaneously controlled HIV-1 replication, the maintenance of a high frequency of functional cT FH cells able to induce broadly neutralizing antibodies (bNabs) against different HIV-1 strains is critical to avoid disease progression.…”

“…23 This phenomenon has been linked to a large number of mutations in variable IgG regions due to the process of somatic hypermutation. 21,25 Since damage in the T FH -cell compartment is an event observed during the acute phase of HIV-1 infection, early antiretroviral (ARV) therapy enables the preservation of T FH function. 22,24 Furthermore, as expected, the maintenance of functional cT FH cells is also associated with a better response to various vaccines in HIV-1-infected patients.…”

“…18,19 This virus-induced dysfunctional T FH -cell expansion not only favors viral persistence and replication but also compromises the ability of patients to produce specific neutralizing antibodies in response to co-infections and vaccines. [20][21][22] By contrast, in a small fraction of patients who spontaneously controlled HIV-1 replication, the maintenance of a high frequency of functional cT FH cells able to induce broadly neutralizing antibodies (bNabs) against different HIV-1 strains is critical to avoid disease progression. 23 This phenomenon has been linked to a large number of mutations in variable IgG regions due to the process of somatic hypermutation.…”

“…22,24 Furthermore, as expected, the maintenance of functional cT FH cells is also associated with a better response to various vaccines in HIV-1-infected patients. 21,25 Since damage in the T FH -cell compartment is an event observed during the acute phase of HIV-1 infection, early antiretroviral (ARV) therapy enables the preservation of T FH function. 16,26 As pregnancy favors maternal humoural immunity, 27 the ARV effects on maternal T FH may help to reduce the risk of mother-to-child viral transmission.…”

State-of-the-art in the pneumococcal field: Proceedings of the 11th International Symposium on Pneumococci and Pneumococcal Diseases (ISPPD-11)

“…Effective protection of immunocompromised individuals against IPD remains a challenge as highlighted in previous sections. It was found that specific adaptive immune cells such as T follicular cells (Tfh) were important for antibody production in response to pneumococcal polysaccharide vaccination [93] but that this was impaired during HIV-infection, whereas an extra PCV13 booster could provide additional benefit among immunocompromised individuals [94].…”