The role of follicular T helper cells in the humoral alloimmune response after clinical organ transplantation

Abstract

Over the past decade, antibody‐mediated or humoral rejection in combination with development of de novo donor‐specific antibodies (DSA) has been recognized as a distinct and common cause of transplant dysfunction and is responsible for one‐third of the failed allografts. Detailed knowledge of the mechanisms that initiate and maintain B‐cell driven antidonor reactivity is required to prevent and better treat this antidonor response in organ transplant patients. Over the past few years, it became evident that this response largely depends on the actions of both T follicular helper (Tfh) cells and the controlling counterparts, the T follicular regulatory (Tfr) cells. In this overview paper, we review the latest insights on the functions of circulating (c)Tfh cells, their subsets Tfh1, Tfh2 and Tfh17 cells, IL‐21 and Tfr cells in antibody mediated rejection (ABMR). This may offer new insights in the process to reduce de novo DSA secretion resulting in a decline in the incidence of ABMR. In addition, monitoring these cell populations could be helpful for the development of biomarkers identifying patients at risk for ABMR and provide novel therapeutic drug targets to treat ABMR.

Coordinated Circulating T Follicular Helper and Activated B Cell Responses Underlie the Onset of Antibody-Mediated Rejection in Kidney Transplantation

“…Mixed-effects model for comparison of %Ki67 1 ICOS 1 cT FH between DSA 1 ABMR 1 or DSA 1 ABMR 2 groups with the DSA Although previous studies have found an association between increased frequencies of PD-1 1 ICOS 1 or PD-1 hi CCR7 lo cT FH and DSA development, their relationship to ABMR was not explored. [31][32][33][34] Interestingly, activated PD-1 hi CCR7 lo cT FH are thought to represent effector memory cells that can rapidly reacquire GC-T FH effector functions upon secondary activation. 35 Here, we identified a novel subset of Ki67 1 ICOS 1 cT FH expressing high levels of CCR7 and CD127, which indicates that these cells are less differentiated than their PD-1 hi CCR7 lo counterparts.…”

Screening and identification of key regulatory connections and immune cell infiltration characteristics for lung transplant rejection using mucosal biopsies

“…Significant differences in the proportions of different subtypes of T cells were consistent with the observations in solid organ transplantation: (1) CD4 + T-cell memory responses were activated during chronic infection following LTx [75] . (2) Activated pro-inflammatory follicular helper T cells promoted the secretion of donor-specific antibodies, resulting in antibody-mediated rejection following kidney transplantation [76] . (3) The levels of anti-inflammatory Tregs decreased in the lung allografts following LTx.…”

CD4 T Helper Cell Subsets and Related Human Immunological Disorders

“…Although the main cytokine produced by Tfh cells is IL-21, it was found that Tfh cells can also secret cytokines that are produced by Th1, Th2, and Th17 cells; therefore, Tfh cells can be classified into Tfh1, Tfh2, and Tfh17 cell subsets [241]. Recently, it has been reported that a new subset of Tfh, which is referred to as Tfh13 cells, have an unusual cytokine profile (IL-13 hi /IL-4 hi /IL-5 hi /IL-21 lo ) and co-express Bcl6 and GATA3 [242].…”