Deficiency of Tfh Cells and Germinal Center in Deceased COVID-19 Patients

Abstract

The COVID-19 pandemic caused by SARS-CoV2 is characterized by a remarkable variation in clinical severity ranging from a mild illness to a fatal multi-organ disease. Understanding the dysregulated human immune responses in the fatal subjects is critical for management of COVID-19 patients and the pandemic. In this study, we examined the immune cell compositions in the lung tissues and hilar lymph nodes using immunohistochemistry on 6 deceased COVID-19 patients and 4 focal organizing pneumonia (FOP) patients who underwent lung surgery and served as controls. We found a dominant presence of macrophages and a general deficiency of T cells and B cells in the lung tissues from deceased COVID-19 patients. In contrast to the FOP patients, Tfh cells and germinal center formation were largely absent in the draining hilar lymph nodes in the deceased COVID-19 patients. This was correlated with reduced IgM and IgG levels compared to convalescent COVID-19 patients. In summary, our data highlight a defect of germinal center structure in deceased COVID-19 patients leading to an impaired humoral immunity. Understanding the mechanisms of this deficiency will be one of the key points for the management of this epidemic.

Impaired ICOS signaling between Tfh and B cells distinguishes hospitalized from ambulatory CoViD-19 patients

“…Deficient ICOS expression and lack of functional ICOS/ICOS-L interactions in humans is associated with common variable immunodeficiency (CVID), which manifests as a decreased in memory class-switched B cells and poor germinal center formation 26, 27 . Defective ICOS-L mediated co-stimulation may be a causal factor in inducing germinal center defects that have been recently reported in severe CoViD-19 15, 16 .…”

“…This delayed B cell response and the subsequent loss of humoral immunity despite a protracted course of disease in CoViD-19 subjects raises concerns over the natural robustness of long-term immunity to SARS-CoV-2 that may mirror waning immunity observed with SARS-CoV-1 30, 31 . Pathological studies in a cohort of deceased CoViD-19 subjects demonstrated a lack of T and B cell responses in lung tissue and a stark ablation of germinal centers within draining hilar lymph nodes 15 . A separate study on lymph node and spleen biopsies demonstrated a similar pattern in live CoViD-19 subjects 16 .…”

“…The paradoxical increase in Tfh cells coupled with B cell lymphopenia and delayed antibody responses suggest impairment of germinal center responses. The absence of intact germinal centers in severe CoViD-19 cases has been recently demonstrated in studies where pathological assessment of hilar lymph nodes in autopsied subjects as well as in lymph node and spleen biopsies from infected subjects were performed 15,16 . Among the mechanisms critical for germinal center formation, in both animal systems and in humans, it is well established that the ICOS-L / ICOS signaling pathway plays a critical role 17,18,19,20,21,22,23 .…”

An Effective COVID-19 Vaccine Needs to Engage T Cells

“…Convalescent patients contain SARS-CoV-2 reactive CD4 T cells (up to 100% of patients) and CD8 T cells (∼70% of patients), including CD4 T FH cells capable of providing help to B cells (29)(30)(31)(32). Consistent with a role for T cells in helping B cells in COVID-19, virus-specific T and T FH cell numbers correlated with nAB and AB titers and deceased COVID-19 patients lacked T FH cells and germinal centers in their draining hilar lymph nodes correlated with reduced AB levels (32)(33)(34)(35)(36)(37). T cell reactivities in recovered patients covered multiple SARS-CoV-2 proteins and particularly targeted immunodominant epitopes in the spike (S), membrane (M), and nucleoproteins (N), indicating a benefit for including these proteins in vaccine designs rather than only S as done in several current vaccines (32,38).…”

Relational interaction between T-lymphocytes and SARS-CoV-2: A review

“…exalted tfh cells in circulation have tracked concurrently with decreasing viral load in non-severe cases (thevarajan et al, 2020). nonetheless, tfh cells deficiency could be seen in secondary lymphoid organs of decedent CoViD-19 cases suggesting kinked antibody maturation may be instrumental in death (Duan et al, 2020). Adult rhesus macaques after being infected with sARs-CoV-2 corroborated assemblage of proliferating, and activated tfh cells in peripheral blood.…”