PD-1^highCXCR5^–CD4⁺ Peripheral Helper T (Tph) cells Promote Tissue-Homing Plasmablasts in COVID-19

Abstract

SummaryA dysregulated immune response against coronavirus-2 (SARS-CoV-2) plays a critical role in the outcome of patients with coronavirus disease 2019 (COVID-19). A significant increase in circulating plasmablasts is characteristic of COVID-19 though the underlying mechanisms and its prognostic implications are not known. Here, we demonstrate that in the acute phase of COVID-19, activated PD-1highCXCR5−CD4+ T cells, peripheral helper T cells, (Tph) are significantly increased and promote inflammatory tissue-homing plasmablasts in patients with stable but not severe COVID-19. Analysis of scRNA-seq data revealed that plasmablasts in stable patients express higher levels of tissue-homing receptors including CXCR3. The increased Tph cells exhibited “B cell help” signatures similar to that of circulating T follicular helper (cTfh) cells and promoted B cell differentiation in vitro. Compared with cTfh cells, Tph cells produced more IFNγ, inducing tissue-homing chemokine receptors on plasmablasts. Finally, expansion of activated Tph cells was correlated with the frequency of CXCR3+ plasmablasts in the acute phase of patients with stable disease. Our results demonstrate a novel role for Tph cells in acute viral immunity by inducing ectopic, antibody secreting plasmablasts.

Virus infection pattern imprinted and diversified the differentiation of T-cell memory in transcription and function

“…The raw data and code were available according to requirements. The public data used for CD28 and CTLA4 transition phase correlation analysis validation were from GSE155223 (44) and GSE180578 (45). Only PBMC samples from COVID-19 patients were considered.…”

T peripheral helper cells in autoimmune diseases*

“…The presence of Tph cells early in clinical autoimmune disease suggests that these cells may play a role in immune responses more generally, rather than being solely the product of a chronic, dysfunctional response. A recent preprint indicates an expansion of Tph cells in patients with acute SARS‐CoV‐2 infection, in which Tph cells demonstrated the ability to stimulate plasmablast differentiation in vitro and correlated with the abundance of tissue‐homing plasmablasts in patients with stable, but not severe, COVID‐19 63 . This suggests that Tph cells can be part of the early adaptive immune response to pathogens, perhaps encouraging differentiation of plasmablasts at extrafollicular sites of T–B cell interaction 64 .…”

“…A recent preprint indicates an expansion of Tph cells in patients with acute SARS-CoV-2 infection, in which Tph cells demonstrated the ability to stimulate plasmablast differentiation in vitro and correlated with the abundance of tissue-homing plasmablasts in patients with stable, but not severe, COVID-19. 63 This suggests that Tph cells can be part of the early adaptive immune response to pathogens, perhaps encouraging differentiation of plasmablasts at extrafollicular sites of T-B cell interaction. 64 Preliminary observations also suggest the potential for baseline Tph cell levels to predict response to COVID-19 vaccination in organ transplant recipients.…”

T cell help in the autoreactive germinal center

“…298,299 Peripheral helper T cells were identified in the synovium of seropositive RA patients and are distinct from cTFH cells due to their PD-1 hi CXCR5 − Bcl6 − profile and ability to migrate to peripheral sites of inflammation. 107,[300][301][302][303] TPH cells produce IL-21 and CXCL13, 304 express TFH signature genes, 289 exhibit hallmarks of exhaustion, 289 can stimulate PB formation in vitro, 289,304,305 and correlate with age-associated CD11c + CD21 − B cell (ABC) levels. 304,306 Antigen-specific TPH cells have been identified in celiac disease and autoimmune hepatitis, 307,308 suggesting that TCR specificity influences TPH fate and possibly function.…”