Implications of MHC-restricted immunopeptidome in transplantation.

The peptide presentation by donor and recipient major histocompatibility complex (MHC) molecules is the major driver of T-cell responses in transplantation. In this review, we address an emerging area of interest, the application of immunopeptidome in transplantation, and describe the potential opportunities that exist to use peptides for targeting alloreactive T cells. The immunopeptidome, the set of peptides presented on an individual's MHC, plays a key role in immune surveillance. In transplantation, the immunopeptidome is heavily influenced by MHC-derived peptides, delineating a key subset of the diverse peptide repertoire implicated in alloreactivity. A better understanding of the immunopeptidome in transplantation has the potential to open up new approaches to identify, characterize, longitudinally quantify, and therapeutically target donor-specific T cells and ultimately support more personalized immunotherapies to prevent rejection and promote allograft tolerance.

Systematic analysis of NLMP suggests nuclear localization of RTK/MET kinases resemble cancer cell clearance.

BACKGROUND: Some membrane proteins can translocate into the nucleus, defined as nuclear localized membrane proteins (NLMPs), including receptor tyrosine kinases (RTKs). We previously showed that nuclear MET (nMET), a member of RTKs, mediates cancer stem-like cells self-renewal to promote cancer recurrence. However, it is unknown that nMET or mMET, which is the ancestor in the evolution of cancer cell survival and clearance. Here, we aim to study the NLMP functions in cell death, differentiation and survival. METHOD: We applied the systematic reanalysis of functional NLMP and clinical investigations of nMET from databases. In addition, we used soft agar assay, immunoblotting, flow cytometry, and immunofluorescence confocal microscopy for examinations of nMET functions including stem-like cell formation, cell signaling, cell cycle regulation, and co-localization with regulators of cell signaling. ShRNA, antibody of recognizing surface membrane MET based treatment were used to downregulate endogenous nMET to uncover its function. RESULTS: We predicted and demonstrated that nMET and nEGFR are most likely not ancestors. nMET overexpression induces both cell death and survival with drug resistance and stem cell-like characters. Moreover, the paradoxical function of nMET in both cell death and cell survival is explained by the fact that nMET induces stem cell-like cell growth, DNA damage repair, to evade the drug sensitization for survival of single cells while non-stem cell-like nMET expressing single cells may undergo clearance by cell death through cell cycle arrest induced by p21. CONCLUSION: Taken together, our data suggest a link between nuclear RTK and cancer cell evolutionary clearance via cell death, and drug resistance for survival through stemness selection. Targeting evolved nuclear RTKs in cancer stem cells would be a novel avenue for precision cancer therapy.