The role of self-peptides in direct T cell allorecognition

Abdelsamed, Hossam; Lakkis, Fadi G.

doi:10.1172/jci154096

Cited by 3 publications

(2 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Over the last decades, alternative pathogenetic concepts have been developed to mechanistically explain direct allorecognition of foreign target cells by T cells. Strikingly, the frequency of alloreactive T cells within a given MHC-mismatched donor is approximately between 1-10%, which is exceptionally high compared to the frequency of T cells specific for a given MHC-peptide complex ( 49 , 50 ). In the light of this finding, the so-called MHC-centric model suggests that polymorphisms in amino acids between self- and allo-MHC molecules affect the manner in which individual TCRs bind to MHC molecules.…”

Section: Discussionmentioning

confidence: 99%

Novel T cell/organoid culture system allows ex vivo modeling of intestinal graft-versus-host disease

Matthe,

Dinkel,

Schmid

et al. 2023

Front. Immunol.

View full text Add to dashboard Cite

Acute graft-versus-host disease (GvHD) remains the biggest clinical challenge and prognosis-determining complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Donor T cells are acceptedly key mediators of alloreactivity against host tissues and here especially the gut. In support of previous studies, we found that the intestinal intra-epithelial lymphocyte (IEL) compartment was dynamically regulated in the course of MHC class I full mismatch allo-HSCT. However, while intestinal epithelial cell (IEC) damage endangers the integrity of the intestinal barrier and is a core signature of intestinal GvHD, the question whether and to what degree IELs are contributing to IEC dysregulation is poorly understood. To study lymphoepithelial interaction, we employed a novel ex vivo T cell/organoid co-culture model system. Here, allogeneic intra-epithelial T cells were superior in inducing IEC death compared to syngeneic IEL and allogeneic non-IEL T cells. The ability to induce IEC death was predominately confined to TCRβ+ T cells and was executed in a largely IFNγ-dependent manner. Alloreactivity required a diverse T cell receptor (TCR) repertoire since IELs genetically modified to express a TCR restricted to a single, non-endogenous antigen failed to mediate IEC pathology. Interestingly, minor histocompatibility antigen (miHA) mismatch was sufficient to elicit IEL-driven IEC damage. Finally, advanced live cell imaging analyses uncovered that alloreactive IELs patrolled smaller areas within intestinal organoids compared to syngeneic controls, indicating their unique migratory properties within allogeneic IECs. Together, we provide here experimental evidence for the utility of a co-culture system to model the cellular and molecular characteristics of the crosstalk between IELs and IEC in an allogeneic setting ex vivo. In the light of the emerging concept of dysregulated immune-epithelial homeostasis as a core aspect of intestinal GvHD, this approach represents a novel experimental system to e.g. screen therapeutic strategies for their potential to normalize T cell/IEC- interaction. Hence, analyses in pre-clinical in vivo allo-HSCT model systems may be restricted to hereby positively selected, promising approaches.

show abstract

Section: Discussionmentioning

confidence: 99%

Novel T cell/organoid culture system allows ex vivo modeling of intestinal graft-versus-host disease

Matthe,

Dinkel,

Schmid

et al. 2023

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…When the allogeneic or donor cells interact with the T-cells, the T-cells proliferate profusely in comparison with the clone populations that target antigens displayed by auto-APC. This mechanism is suggested in acute allorejection [73].…”

Section: Direct Pathway/mechanismmentioning

confidence: 90%

Classic and Current Opinions in Human Organ and Tissue Transplantation

Oli¹,

Rowaiye²,

Adejumo³

et al. 2022

Cureus

View full text Add to dashboard Cite

Graft tolerance is a pathophysiological condition heavily reliant on the dynamic interaction of the innate and adaptive immune systems. Genetic polymorphism determines immune responses to tissue/organ transplantation, and intricate humoral and cell-mediated mechanisms control these responses. In transplantation, the clinician's goal is to achieve a delicate equilibrium between the allogeneic immune response, undesired effects of the immunosuppressive drugs, and the existing morbidities that are potentially life-threatening. Transplant immunopathology involves sensitization, effector, and apoptosis phases which recruit and engages immunological cells like natural killer cells, lymphocytes, neutrophils, and monocytes. Similarly, these cells are involved in the transfer of normal or genetically engineered T cells. Advances in tissue transplantation would involve a profound knowledge of the molecular mechanisms that underpin the respective immunopathology involved and the design of precision medicines that are safe and effective.

show abstract