Role of chemokines and their receptors in lesional CD8⁺ T cell homing in Indian Post-Kala-Azar Dermal Leishmaniasis

BACKGROUND: Post-kala-azar dermal leishmaniasis (PKDL), a dermal sequel of visceral leishmaniasis (VL) is considered as a reservoir that facilitates the transmission of VL. Although PKDL lesions demonstrate an overwhelming infiltration of CD8 ⁺ T cells, characterization of lesional CD8 ⁺ T cells, their tissue-homing chemokine receptors and corresponding ligands remains poorly defined, and was the aim of this study. METHODOLOGY: In patients with PKDL, CD8 ⁺ T cells were phenotyped in skin biopsies, in terms of senescence (CD8 ⁺ /CD57⁺), and cytotoxicity (expression of Perforin and Granzyme). The plasma levels of T cell chemoattractants (CCL3/4/5/17, CXCL9/10), and associated cytokines (IFN-γ, IL-5, TNF-α, IL-15) were assessed by a multiplex assay, while their lesional expression was evaluated by bulk RNA sequencing and immunohistochemistry. Furthermore, the expression of circulating chemokine receptors, namely CCR4 (for CCL17/22), CCR5 (for CCL3), and CXCR3 (for CXCL9/10), were assessed by flow cytometry, and at lesional sites using transcriptomic data/immunofluorescence. PRINCIPAL FINDINGS: As compared to healthy controls, dermal lesions from PKDL patients showed a significant increase in CD8 ⁺ T cells that demonstrated exhaustion/senescence (CD8 ⁺ /CD57⁺), as also lacked Perforin and Granzyme. In circulation and lesional tissues, T cell chemoattractants (CCL 3/4/5/17, CXCL 9/10) and pro-inflammatory cytokines (IFN-γ, IL-5, IL-15 TNF-α) along with their corresponding receptors, CCR4, CCR5 and CXCR3 were elevated. CONCLUSIONS: In dermal lesions of PKDL, an enhanced homing of CD8 ⁺ T cells was achieved via an upregulation of T cell chemoattractants CCL3/4/5/17, CXCL9/10, and their corresponding receptors. Their exhausted/senescent phenotype and loss of cytotoxicity possibly facilitated parasite persistence, highlighting the need for host directed immunotherapeutic approaches aimed at restoring T cell potency.