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Altered IL-7 signaling in CD4+ T cells from patients with visceral leishmaniasis.
- Source :
- PLoS Neglected Tropical Diseases; 2/26/2024, Vol. 18 Issue 2, p1-16, 16p
- Publication Year :
- 2024
-
Abstract
- Background: CD4<superscript>+</superscript> T cells play a central role in control of L. donovani infection, through IFN-γ production required for activation of macrophages and killing of intracellular parasites. Impaired control of parasites can in part be explained by hampered CD4<superscript>+</superscript> T cells effector functions in visceral leishmaniasis (VL) patients. In a recent studies that defined transcriptional signatures for CD4<superscript>+</superscript> T cells from active VL patients, we found that expression of the IL-7 receptor alpha chain (IL-7Rα; CD127) was downregulated, compared to CD4<superscript>+</superscript> T cells from endemic controls (ECs). Since IL-7 signaling is critical for the survival and homeostatic maintenance of CD4<superscript>+</superscript> T cells, we investigated this signaling pathway in VL patients, relative to ECs. Methods: CD4<superscript>+</superscript> T cells were enriched from peripheral blood collected from VL patients and EC subjects and expression of IL7 and IL7RA mRNA was measured by real time qPCR. IL-7 signaling potential and surface expression of CD127 and CD132 on CD4<superscript>+</superscript> T cell was analyzed by multicolor flow cytometry. Plasma levels of soluble IL-7 and sIL-7Rα were measured by ELISA. Result: Transcriptional profiling data sets generated previously from our group showed lower IL7RA mRNA expression in VL CD4<superscript>+</superscript> T cells as compared to EC. A significant reduction was, however not seen when assessing IL7RA mRNA by RT-qPCR. Yet, the levels of soluble IL-7Rα (sIL-7Rα) were reduced in plasma of VL patients compared to ECs. Furthermore, the levels of soluble IL-7 were higher in plasma from VL patients compared to ECs. Interestingly, expression of the IL-7Rα protein was higher on VL patient CD4<superscript>+</superscript> T cells as compared to EC, with activated CD38<superscript>+</superscript> CD4<superscript>+</superscript> T cells showing higher surface expression of IL-7Rα compared to CD38<superscript>-</superscript> CD4<superscript>+</superscript> T cells in VL patients. CD4<superscript>+</superscript> T cells from VL patients had higher signaling potential baseline and after stimulation with recombinant human IL-7 (rhIL-7) compared to EC, as measured by phosphorylation of STAT5 (pSTAT5). Interestingly, it was the CD38 negative cells that had the highest level of pSTAT5 in VL patient CD4<superscript>+</superscript> T cells after IL-7 stimulation. Thus, despite unaltered or potentially lowered IL7RA mRNA expression by CD4<superscript>+</superscript> T cells from VL patients, the surface expression of the IL-7Rα was higher compared to EC and increased pSTAT5 was seen following exposure to rhIL-7. Accordingly, IL-7 signaling appears to be functional and even enhanced in VL CD4<superscript>+</superscript> T cells and cannot explain the impaired effector function of VL CD4<superscript>+</superscript> T cells. The enhanced plasma IL-7 may serve as part of homeostatic feedback mechanism regulating IL7RA expression in CD4<superscript>+</superscript> T cells. Author summary: In visceral leishmaniasis (VL), antigen specific CD4<superscript>+</superscript> T cell responses are muted hindering the control of the Leishmania donovani infection. IL-7 signaling is crucial for CD4<superscript>+</superscript> T cell survival and function, and gene expression analysis indicated that the IL-7 pathway could be altered in VL. Thus, we investigate if impaired IL-7 signaling could explain the loss of antigen specific T cell response in VL. Although we didn't observe significant reduction of IL7RA mRNA by RT-qPCR, yet, the levels of soluble IL-7Rα (sIL-7Rα) were reduced in plasma of VL patients compared to ECs. Furthermore, the levels of soluble IL-7 were higher in plasma from VL patients compared to ECs and their CD4<superscript>+</superscript> T cells exhibited heightened IL-7 receptor protein expression. Surprisingly, VL patient CD4<superscript>+</superscript> T cells showed increased IL-7 signaling potential, as evidenced by higher phosphorylation of STAT5 upon IL-7 stimulation. While altered, the findings presented here do not attributed the impaired effector function of VL CD4<superscript>+</superscript> T cells to defective IL-7 signaling. We speculate that the elevated plasma IL-7 is part of a homeostatic feedback mechanism in response to the reduced IL7RA transcription in CD4<superscript>+</superscript> T cells. [ABSTRACT FROM AUTHOR]
- Subjects :
- T cells
VISCERAL leishmaniasis
GENE expression
LEISHMANIA donovani
CELL physiology
Subjects
Details
- Language :
- English
- ISSN :
- 19352727
- Volume :
- 18
- Issue :
- 2
- Database :
- Complementary Index
- Journal :
- PLoS Neglected Tropical Diseases
- Publication Type :
- Academic Journal
- Accession number :
- 175675355
- Full Text :
- https://doi.org/10.1371/journal.pntd.0011960