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Limited TCR repertoire and ENTPD1 dysregulation mark late-stage COVID-19.

ABSTRACT: T cell exhaustion and dysfunction are hallmarks of severe COVID-19. To gain insights into the pathways underlying these alterations, we performed a comprehensive transcriptome analysis of peripheral-blood-mononuclear-cells (PBMCs), spleen, lung, kidney, liver, and heart obtained at autopsy from COVID-19 patients and matched controls, using the nCounter CAR-T-Characterization panel. We found substantial gene alterations in COVID-19-impacted organs, especially the lung where altered TCR repertoires are noted. Reduced TCR repertoires are also observed in PBMCs of severe COVID-19 patients. ENTPD1/CD39, an ectoenzyme defining exhausted T-cells, is upregulated in the lung, liver, spleen, and PBMCs of severe COVID-19 patients where expression positively correlates with markers of vasculopathy. Heightened ENTPD1/CD39 is paralleled by elevations in STAT-3 and HIF-1α transcription factors; and by markedly reduced CD39-antisense-RNA, a long-noncoding-RNA negatively regulating ENTPD1/CD39 at the post-transcriptional level. Limited TCR repertoire and aberrant regulation of ENTPD1/CD39 could have permissive roles in COVID-19 progression and indicate potential therapeutic targets to reverse disease.

SUBMITTER: Wang N

PROVIDER: S-EPMC8482538 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Human immunodeficiency virus 1 (HIV-1) infection is associated with a vigorous cellular immune response that allows detection of cytotoxic T lymphocyte (CTL) activity using freshly isolated peripheral blood mononuclear cells (PBMC). Although restricting class I antigens and epitopes recognized by HIV-1-specific CTL have been defined, the effector cells mediating this vigorous response have been characterized less well. Specifically, no studies have addressed the breadth and duration of response to a defined epitope. In the present study, a longitudinal analysis of T cell receptor (TCR) gene usage by CTL clones was performed in a seropositive person using TCR gene sequences as a means of tracking responses to a well-defined epitope in the glycoprotein 41 transmembrane protein. 10 CTL clones specific for this human histocompatibility leukocyte antigen-B14-restricted epitope were isolated at multiple time points over a 31-mo period. All clones were derived from a single asymptomatic HIV-1-infected individual with a vigorous response to this epitope that was detectable using unstimulated PBMC. Polymerase chain reaction amplification using V alpha and V beta family-specific primers was performed on each clone, followed by DNA sequencing of the V-D-J regions. All 10 clones utilized V alpha 14 and V beta 4 genes. Sequence analysis of the TCR revealed the first nine clones isolated to also be identical at the nucleotide level. The TCR-alpha junctional region sequence of the tenth clone was identical to the junctional region sequences of the other nine, but this clone utilized distinct D beta and J beta gene segments. This study provides evidence that the observed high degree of HIV-1-specific CTL activity may be due to monoclonal or oligoclonal expansion of specific effector cells, and that progeny of a particular CTL clone may persist for prolonged periods in vivo in the presence of a chronic productive viral infection. The observed limited TCR diversity against an immunodominant epitope may limit recognition of virus variants with mutations in regions interacting with the TCR, thereby facilitating immune escape.

Project description:A broad T cell receptor (TCR-) repertoire is required for an effective immune response. TCR-repertoire diversity declines with age. End-stage renal disease (ESRD) patients have a prematurely aged T cell system which is associated with defective T cell-mediated immunity. Recently, we showed that ESRD may significantly skew the TCR V?-repertoire. Here, we assessed the impact of ESRD on the TCR V?-repertoire within different T cell subsets using a multiparameter flow-cytometry-based assay, controlling for effects of aging and CMV latency. Percentages of 24 different TCR V?-families were tested in circulating naive and memory T cell subsets of 10 ESRD patients and 10 age- and CMV-serostatus-matched healthy individuals (HI). The Gini-index, a parameter used in economics to describe the distribution of income, was calculated to determine the extent of skewing at the subset level taking into account frequencies of all 24 TCR V?-families. In addition, using HI as reference population, the differential impact of ESRD was assessed on clonal expansion at the level of an individual TCR V?-family. CD8+, but not CD4+, T cell differentiation was associated with higher Gini-TCR indices. Gini-TCR indices were already significantly higher for different CD8+ memory T cell subsets of younger ESRD patients compared to their age-matched HI. ESRD induced expansions of not one TCR V?-family in particular and expansions were predominantly observed within the CD8+ T cell compartment. All ESRD patients had expanded TCR V?-families within total CD8+ T cells and the median (IQ range) number of expanded TCR V?-families/patient amounted to 2 (1-4). Interestingly, ESRD also induced clonal expansions of TCR V?-families within naive CD8+ T cells as 8 out of 10 patients had expanded TCR V?-families. The median (IQ range) number of expanded families/patient amounted to 1 (1-1) within naive CD8+ T cells. In conclusion, loss of renal function skews the TCR V?-repertoire already in younger patients by inducing expansions of different TCR V?-families within the various T cell subsets, primarily affecting the CD8+ T cell compartment. This skewed TCR V?-repertoire may be associated with a less broad and diverse T cell-mediated immunity.

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Limited TCR repertoire and ENTPD1 dysregulation mark late-stage COVID-19.

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