Dataset Information

Non-pathogenic tissue-resident CD8⁺ T cells uniquely accumulate in the brains of lupus-prone mice.

ABSTRACT: Severe lupus often includes psychiatric and neurological sequelae, although the cellular contributors to CNS disease remain poorly defined. Using intravascular staining to discriminate tissue-localized from blood-borne cells, we find substantial accumulation of CD8⁺ T cells relative to other lymphocytes in brain tissue, which correlates with lupus disease and limited neuropathology. This is in contrast to all other affected organs, where infiltrating CD4⁺ cells are predominant. Brain-infiltrating CD8⁺ T cells represent an activated subset of those found in the periphery, having a resident-memory phenotype (CD69⁺CD122^-PD1⁺CD44⁺CD62L^-) and expressing adhesion molecules (VLA-4⁺LFA-1⁺) complementary to activated brain endothelium. Remarkably, infiltrating CD8⁺ T cells do not cause tissue damage in lupus-prone mice, as genetic ablation of these cells via β2 m deficiency does not reverse neuropathology, but exacerbates disease both in the brain and globally despite decreased serum IgG levels. Thus, lupus-associated inflammation disrupts the blood-brain barrier in a discriminating way biased in favor of non-pathogenic CD8⁺ T cells relative to other infiltrating leukocytes, perhaps preventing further tissue damage in such a sensitive organ.

SUBMITTER: Morawski PA

PROVIDER: S-EPMC5241651 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Non-pathogenic tissue-resident CD8+ T cells uniquely accumulate in the brains of lupus-prone mice.

Morawski Peter A PA Qi Chen-Feng CF Bolland Silvia S

Scientific reports 20170118

Severe lupus often includes psychiatric and neurological sequelae, although the cellular contributors to CNS disease remain poorly defined. Using intravascular staining to discriminate tissue-localized from blood-borne cells, we find substantial accumulation of CD8+ T cells relative to other lymphocytes in brain tissue, which correlates with lupus disease and limited neuropathology. This is in contrast to all other affected organs, where infiltrating CD4+ cells are predomin ...[more]

PMID: 28098193

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Project description:IntroductionDespite recent advances in immunotherapy for hepatocellular carcinoma (HCC), the overall modest response rate underscores the need for a better understanding of the tumor microenvironment (TME) of HCC. We have previously shown that CD38 is widely expressed on tumor-infiltrating leukocytes (TILs), predominantly on CD3+ T cells and monocytes. However, its specific role in the HCC TME remains unclear.MethodsIn this current study, we used cytometry time-of-flight (CyTOF), bulk RNA sequencing on sorted T cells, and single-cell RNA (scRNA) sequencing to interrogate expression of CD38 and its correlation with T cell exhaustion in HCC samples. We also employed multiplex immunohistochemistry (mIHC) for validating our findings.ResultsFrom CyTOF analysis, we compared the immune composition of CD38-expressing leukocytes in TILs, non-tumor tissue-infiltrating leukocytes (NIL), and peripheral blood mononuclear cells (PBMC). We identified CD8+ T cells as the dominant CD38-expressing TILs and found that CD38 expression was significantly higher in CD8+ TRM in TILs than in NILs. Furthermore, through transcriptomic analysis on sorted CD8+ TRM from HCC tumors, we observed a higher expression of CD38 along with T cell exhaustion genes, including PDCD1 and CTLA4, compared to the circulating memory CD8 T cells from PBMC. This was validated by scRNA sequencing that revealed co-expression of CD38 with PDCD1, CTLA4, and ITGAE (CD103) in T cells from HCC tumors. The protein co-expression of CD38 and PD-1 on CD8+ T cells was further demonstrated by mIHC on HCC FFPE tissues, marking CD38 as a T cell co-exhaustion marker in HCC. Lastly, the higher proportions of CD38+PD-1+ CD8+ T cells and CD38+PD-1+ TRM were significantly associated with the higher histopathological grades of HCC, indicating its role in the aggressiveness of the disease.ConclusionTaken together, the concurrent expression of CD38 with exhaustion markers on CD8+ TRM underpins its role as a key marker of T cell exhaustion and a potential therapeutic target for restoring cytotoxic T cell function in HCC.

Dataset Information

Non-pathogenic tissue-resident CD8⁺ T cells uniquely accumulate in the brains of lupus-prone mice.

Publications

Non-pathogenic tissue-resident CD8<sup>+</sup> T cells uniquely accumulate in the brains of lupus-prone mice.

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