Destruction of the host intestinal epithelium by donor effector T cell populations is a hallmark of graft-versus-host disease (GVHD), but the underlying mechanisms remain obscure. We demonstrate that CD8+ T cells expressing CD103, an integrin conferring specificity for the epithelial ligand E-cadherin, play a critical role in this process. A TCR transgenic GVHD model was used to demonstrate that CD103 is selectively expressed by host-specific CD8+ T cell effector populations (CD8 effectors) that accumulate in the host intestinal epithelium during GVHD. Although host-specific CD8 effectors infiltrated a wide range of host compartments, only those infiltrating the intestinal epithelium expressed CD103. Host-specific CD8 effectors expressing a TGF-β dominant negative type II receptor were defective in CD103 expression on entry into the intestinal epithelium, which indicates local TGF-β activity as a critical regulating factor. Host-specific CD8 effectors deficient in CD103 expression successfully migrated into the host intestinal epithelium but were retained at this site much less efficiently than wild-type host-specific CD8 effectors. The relevance of these events to GVHD pathogenesis is supported by the finding that CD103-deficient CD8+ T cells were strikingly defective in transferring intestinal GVHD pathology and mortality. Collectively, these data document a pivotal role for TGF-β–dependent CD103 expression in dictating the gut tropism, and hence the destructive potential, of CD8+ T cells during GVHD pathogenesis.

CD103 is an integrin with specificity for the epithelial cell-specific ligand, E-cadherin. Recent studies indicate that CD103 expression endows peripheral CD8 cells with a unique capacity to access the epithelial compartments of organ allografts. In the present study we used a nonvascularized mouse renal allograft model to 1) define the mechanisms regulating CD103 expression by graft-infiltrating CD8 effector populations, and 2) identify the cellular compartments in which this occurs. We report that CD8 cells responding to donor alloantigens in host lymphoid compartments do not initially express CD103, but dramatically up-regulate CD103 expression to high levels subsequent to migration to the graft site. CD103+CD8+ cells that infiltrated renal allografts exhibited a classic effector phenotype and were selectively localized to the graft site. CD8 cells expressing low levels of CD103 were also present in lymphoid compartments, but three-color analyses revealed that these are almost exclusively of naive phenotype. Adoptive transfer studies using TCR-transgenic CD8 cells demonstrated that donor-specific CD8 cells rapidly and uniformly up-regulate CD103 expression following entry into the graft site. Donor-specific CD8 cells expressing a dominant negative TGF-β receptor were highly deficient in CD103 expression following migration to the graft, thereby implicating TGF-β activity as a dominant controlling factor. The relevance of these data to conventional (vascularized) renal transplantation is confirmed. These data support a model in which TGF-β activity present locally at the graft site plays a critical role in regulating CD103 expression, and hence the epitheliotropism, of CD8 effector populations that infiltrate renal allografts.

Immune destruction of the graft renal tubules is an important barrier to the long-term function of clinical renal allografts, but the underlying mechanisms remain obscure. CD103—an integrin conferring specificity for the epithelial cell-restricted ligand, E-cadherin—defines a subset of CD8 effectors that infiltrate the graft tubular epithelium during clinical rejection episodes, predicting a causal role for CD103+CD8+ effectors in tubular injury. In the present study, we used rodent transplant models to directly test this hypothesis. Surprisingly, CD8 cells infiltrating renal allografts undergoing unmodified acute rejection did not express significant levels of CD103. However, we demonstrate that a brief course of cyclosporine A to rat renal allograft recipients promotes progressive accumulation of CD103+CD8+ cells within the graft, concomitant with the development of tubular atrophy and interstitial fibrosis. As in the known clinical scenario, graft-associated CD103+CD8+ cells exhibited a T effector phenotype and were intimately associated with the renal tubular epithelium. Treatment with anti-CD103 mAb dramatically attenuated CD8 infiltration into the renal tubules and tubular injury. Mouse studies documented that CD103 expression is required for efficient destruction of the graft renal tubules by CD8 effectors directed to donor MHC I alloantigens. Taken together, these data document a causal role for CD103+CD8+ effectors in promoting tubular injury following allogeneic renal transplantation and identify novel targets for therapeutic intervention in this important clinical problem.

Severity of symptoms in COVID-19 has been shown to result from a cytokine storm. Interleukin (IL)-17 is one of these various cytokines, which results in a proinflammatory response, systemic inflammatory symptoms, inflammatory cell infiltration of lung tissue and thus leads to the massive lung pathology and multiorgan failure. Gene polymorphisms in the regulatory regions of cytokine-encoding genes affect the amounts of cytokines produced and possess a fundamental role in infectious diseases. This study aimed to investigate the role of IL-17A (rs2275913; G197A) gene polymorphism as predictor of disease severity and its correlation with IL-17 serum levels in COVID-19 patients. A group of 70 COVID-19 patients and 17 age and sex-matched control subjects were enrolled in the present work. Patients were classified into two groups moderate, severe and acute respiratory distress (ARDS) cases, defined according to the criteria established by the world health organization. Quantitative real time-polymerase chain reaction was done to detect IL-17A (rs2275913; G197A). Serum IL-17 levels were assessed by an enzyme-linked immunosorbent assay in both patients and controls. The distribution of different IL-17A G/A genotypes among COVID-19 patients were 44.3% for GG genotype, 44.3% for AG genotype and 11.4% for AA genotype. Genotypes among the control group were 43.8% for GG genotype, 50% for AG genotype and 6.3% for AA genotype. G allele distribution was 66.4%, 68.8% in patient and control group, respectively, and A allele was 33.6% and 31.3%, respectively. There was no association between the different genotypes, disease severity or IL-17 serum levels in the patient group. In conclusion, despite the possible role of IL-17 in the pathogenesis of inflammation, there was no association between IL-17 polymorphism and disease severity or IL-17 serum levels among Egyptian COVID-19 patients.

Coagulase-negative staphylococci (CoNS) are frequently isolated from wound infections. There are limited data examining the prevalence of methicillin-resistant CoNS (MRCoNS) among Egyptian patients after surgery. Thus, we studied 208 hospitalised patients, who had skin and soft tissue infections (SSTIs) due to various causes. Samples were cultured for isolation and identification of CoNS and isolates were screened for susceptibility against 23 different antimicrobials. Out of 241 Staphylococcal isolates, 114 (47.3%) were CoNS. The prevalence of MRCoNS among surgical site infection, diabetic foot, abscess, and burn patients was 13.4%, 11.5%, 15.6%, and 10.3%, respectively. The lowest resistance of the 27 identified MRCoNS isolates was to vancomycin, amikacin and gatifloxacin (7% each). We conclude that CoNS isolates are major pathogens associated with wound infections at our institution and MRCoNS probably poses a substantial threat for patients in Egypt, though most MRCoNS isolates demonstrated susceptibility to vancomycin.

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