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LAG-3- and CXCR5-expressing CD4 T cells display progenitor-like properties during chronic visceral leishmaniasis

ABSTRACT: In chronic infections, sustaining the CD4 T cell responses is crucial for pathogen clearance. The expression of inhibitory receptors such as LAG-3 or Lymphocyte activation gene 3 is usually associated with immune suppression and T cell exhaustion. However, LAG-3 also serves as an immune checkpoint molecule and is implicated in proliferation control and cell survival. In this study, we have utilized a mouse model of visceral leishmaniasis (VL), to characterize a subset of LAG-3- and CXCR5-expressing CD4 T cells. These LAG-3+CXCR5+PD-1lo/int CD4 T cells exist in naïve mice, they expand during VL, and are antigen specific. Importantly, the RNAseq analysis showed that these cells highly express gene signatures associated with self-renewal capacity, indicating that these cells might act as progenitors. Additionally, upon adoptive transfer into Rag1-/- mice followed by challenge with Leishmania donovani, these LAG-3+CXCR5+ PD-1lo/int CD4 T cells gave rise to different types of T effector and regulatory subsets, demonstrating their differentiation potential. These cells were also observed in mice infected with LCMV clone-13 and Heligmosomoides polygyrus bakeri. In summary, we propose that these LAG-3+CXCR5+ PD-1lo/int CD4 T cells that exhibit progenitor-like capacities could be implicated in maintaining CD4 T cell responses in chronic infections.

ORGANISM(S): Mus musculus

PROVIDER: GSE255333 | GEO | 2024/02/13

REPOSITORIES: GEO

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Project description:Introduction Immune checkpoint blockade (ICB) is a systemic therapeutic option for advanced hepatocellular carcinoma (HCC). However, low patient response rates necessitate the development of robust predictive biomarkers that identify individuals who will benefit from ICB. A 4-gene inflammatory signature, comprising CD8, PD-L1, LAG-3, and STAT1, was recently shown to be associated with a better overall response to ICB in various cancer types. Here, we examined whether tissue protein expression of CD8, PD-L1, LAG-3, and STAT1 predicts response to ICB in HCC. Methods HCC samples from 191 Asian patients, comprising resection specimens from 124 patients (ICB-naïve) and pre-treatment specimens from 67 advanced HCC patients treated with ICB (ICB-treated), were analyzed for CD8, PD-L1, LAG-3, and STAT1 tissue expression using multiplex immunohistochemistry followed by statistical and survival analyses. Results Immunohistochemical and survival analyses of ICB-naïve samples showed that high LAG-3 expression was associated with shorter median progression-free survival (mPFS) and overall survival (mOS). Analysis of ICB-treated samples revealed that high proportions of LAG-3+ and LAG-3+CD8+ cells pre-treatment were most closely associated with longer mPFS and mOS. Using a log-likelihood model, adding the total LAG-3+ cell proportion to the total CD8+ cell proportion significantly increased the predictive values for mPFS and mOS, compared with the total CD8+ cell proportion alone. Moreover, levels of CD8 and STAT1, but not PD-L1, were significantly correlated with better responses to ICB. After analyzing viral-related and non-viral HCC samples separately, only the LAG3+CD8+ cell proportion was significantly associated with responses to ICB regardless of viral status. Conclusion Immunohistochemical scoring of pre-treatment levels of LAG-3 and CD8 in the tumor microenvironment may help predict ICB benefits in HCC patients. Furthermore, immunohistochemistry-based techniques offer the advantage of being readily translatable in the clinical setting.

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LAG-3- and CXCR5-expressing CD4 T cells display progenitor-like properties during chronic visceral leishmaniasis

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