TIGIT regulates apoptosis of risky memory T cell subsets implicated in belatacept-resistant rejection

Abstract

Transplantation is a curative, life-saving therapy for end-stage organ failure. However, the incidence of significant morbidity and graft loss due to immunosuppression-induced toxicities remains unacceptably high. 1,2 CD28 costimulation blockade in the form of belatacept is a CTLA-4Ig fusion protein and the first new primary immunosuppressive agent in transplantation in over 20 years. 3,4 Belatacept offers a significant benefit to renal transplant recipients in that it carries a 43% reduced risk of death or graft loss after 7 years as compared to calcineurin inhibitor-based regimens. 5 Nonetheless, belatacept confers a significantly increased risk of acute rejection as compared to calcineurin inhibitors, [6][7][8] a fact that has limited its uptake in the clinical transplant community. Our work and that of many others has revealed that belatacept-resistant rejection is likely the result of the activation of memory T cells that have a diminished requirement for CD28 signaling. [9][10][11][12] The resistance of memory T cells to the effects

Three-dimensional imaging and single-cell transcriptomics of the human kidney implicate perturbation of lymphatics in alloimmunity

“…Lymphatics display a distinct molecular profile from their blood vascular counterparts in chronic rejection, expressing immune inhibitory molecules with the potential to regulate local alloreactive CD4 + T cells. These findings, akin to those recently delineated for mouse tumour (Gkountidi et al 2021;Steele et al 2022), central nervous system (Hsu et al 2022) and dermal lymphatics (Churchill et al 2022), suggest lymphatics modulate adaptive immune responses within the tissue microenvironment, beyond their roles in leukocyte egress; implicating these vessels as an emerging therapeutic target in chronic transplant rejection (Gupta et al 2012;Sun et al 2021).…”

Emergence of a senescent and inflammatory pulmonary CD4+T cell population prior to lung allograft failure

“…Accumulating evidence has revealed an association of CD4 + CD57 + T cells – with or without associated PD-1 expression – with autoimmune diseases, infectious diseases, and cancers 44 . CD4 + CD57 + T cells have been detected in the peripheral blood of kidney transplant recipients undergoing rejection 45 , particularly in costimulation blockade resistant rejection 46,47 . Of note, the CD4 + CD57 + T cells associated with rejection in kidney transplantation were measured in the PBMC and exhibit low expression of PD1.…”

Identification of Colon Immune Cell Marker Genes Using Machine Learning Methods

“…The mRMR identified TIGIT , which has been widely recognized in various T cell subtypes [ 59 , 60 ]. Differentially expressed TIGIT has been observed in central memory T cells, even compared to other cell types [ 59 , 61 ].…”