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Altered IL-7 signaling in CD4+ T cells from patients with visceral leishmaniasis.
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- Author(s): Kumar, Shashi1 (AUTHOR); Chauhan, Shashi Bhushan2 (AUTHOR); Upadhyay, Shreya1 (AUTHOR); Singh, Siddharth Sankar3 (AUTHOR); Verma, Vimal1 (AUTHOR); Kumar, Rajiv4 (AUTHOR) ; Engwerda, Christian5 (AUTHOR); Nylén, Susanne6 (AUTHOR) ; Sundar, Shyam1 (AUTHOR)
- Source:
PLoS Neglected Tropical Diseases. 2/26/2024, Vol. 18 Issue 2, p1-16. 16p.- Subject Terms:
- Source:
- Additional Information
- Abstract: Background: CD4+ 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+ T cells effector functions in visceral leishmaniasis (VL) patients. In a recent studies that defined transcriptional signatures for CD4+ 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+ T cells from endemic controls (ECs). Since IL-7 signaling is critical for the survival and homeostatic maintenance of CD4+ T cells, we investigated this signaling pathway in VL patients, relative to ECs. Methods: CD4+ 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+ 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+ 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+ T cells as compared to EC, with activated CD38+ CD4+ T cells showing higher surface expression of IL-7Rα compared to CD38- CD4+ T cells in VL patients. CD4+ 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+ T cells after IL-7 stimulation. Thus, despite unaltered or potentially lowered IL7RA mRNA expression by CD4+ 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+ T cells and cannot explain the impaired effector function of VL CD4+ T cells. The enhanced plasma IL-7 may serve as part of homeostatic feedback mechanism regulating IL7RA expression in CD4+ T cells. Author summary: In visceral leishmaniasis (VL), antigen specific CD4+ T cell responses are muted hindering the control of the Leishmania donovani infection. IL-7 signaling is crucial for CD4+ 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+ T cells exhibited heightened IL-7 receptor protein expression. Surprisingly, VL patient CD4+ 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+ 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+ T cells. [ABSTRACT FROM AUTHOR]
- Abstract: Copyright of PLoS Neglected Tropical Diseases is the property of Public Library of Science and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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