Chemokines Signature and T Cell Dynamics in Leishmaniasis: Molecular insight and therapeutic application

Abstract

Leishmaniasis, caused by obligate intracellular Leishmania parasites, poses a significant global health burden. The control of Leishmania infection relies on an effective T cell-dependent immune response; however, various factors impede the host’s ability to mount a successful defence. Alterations in the chemokine profile, responsible for cell trafficking to the infection site, can disrupt optimal immune responses and influence the outcome of pathogenesis by facilitating parasite persistence. This review aims to emphasize the significance of the chemokine system in T cell responses and to summarize the current knowledge on the dysregulation of chemokines and their receptors associated with different subsets of T lymphocytes during Leishmaniasis. A comprehensive understanding of the dynamic nature of the chemokine system during Leishmaniasis is crucial for the development of successful immunotherapeutic approaches.

Figure 1.

Chemokine signalling pathway. Chemokine receptor (CKR) remains in an inactive stage in which chemokine is not associated with it, and G-protein is in an inactive state and bound with GDP. CKR on interaction with specific chemokine triggers the activation of the bound heterotrimeric G-protein composed of αβγ subunits which leads to an exchange of GDP with GTP and dissociation of the heterotrimeric G protein complex into Gα and Gβγ subunits where GTP remains attached to Gα subunit. Depending on the nature of the inducing signal and types of Gα protein, different signalling pathways get activated. (a) Gα_i inhibits the activity of adenylate cyclase enzyme and reduces the cAMP generation; (b) Gα_s stimulate the activity of adenylate cyclase enzyme and stimulates the production of cAMP which further activates PKA; (c) Gα_12/13 activates rho-family GTPase and regulate the actin cytoskeleton remodelling; (d) Gα_q (or Gβγ) activate PLC-β enzyme which cleaves PIP2, located in the plasma membrane, into DAG molecules and intracellular secondary messenger IP3. DAG further activate PKC and IP3 binds to its receptor on endoplasmic reticulum (ER) causing Ca²⁺ release into the cytoplasm; (d) Gβγ can also activate the Akt pathway, MAP kinase pathway, and Ca²⁺ dependent pathway. (d) Both the Gα and Gβγ subunits are capable of initiating a downstream signalling cascade that results in a range of cellular activities, including changes in cytoskeleton dynamics and cell migration that ultimately regulate the physiological and pathological response of the cells.

Figure 2.

Activation and differentiation of CD4 ⁺ T and CD8 ⁺ T cell subsets during leishmaniasis. Leishmania antigens are presented by APCs or infected macrophages (1,2) to naïve CD4⁺ T cells through MHC class II molecules, leading to their activation. Depending on the cytokine environment, naïve CD4⁺ T cells can differentiate into various T-helper subsets (3). Interleukin-12 (IL-12) facilitates the differentiation of Th1 cells, which produce IFN-γ and TNF-α, promoting the clearance of intracellular parasites. Th17 cells, on the other hand, produce IL-17 and IL-22, contributing to anti-leishmanial and inflammatory responses (4). Th2 cell differentiation occurs under the influence of IL-4, leading to the production of IL-10 and IL-4 which can result in parasite persistence by inhibiting macrophage activation. Similarly, TGF-β promotes the differentiation of T-regs, which produce IL-10 and TGF-β, contributing to immune regulation and further supporting parasite persistence (5). Naïve CD8⁺ T cells are activated via MHC class I molecules and can differentiate into CTLs, producing perforin and granzyme B to target infected cells. They also produce IFN-γ and TNF-α, which support the Th1 response for effective parasite clearance (6). [CTL- Cytotoxic T lymphocytes, APC- Antigen presenting cell, MHC- Major Histocompatibility complex, Gzm B-Granzyme-B, TGF β- transforming growth factor-β, T-regs - Regulatory T cells].

Figure 3.

Formation of Granuloma. Granulomas are formed as a response to infection, such as around Kupffer cells in the liver, to elicit a targeted immune response to eliminate parasites and prevent dissemination. Kupffer cells post-infection via phagocytosis (a) get activated and thereafter release chemokines such as CCL2, CCCL3, and CXCL10 that assist in the recruitment of immune cells like monocytes, T cells, neutrophils, and iNKT cells to the site of infection (b) leading to accumulations of the immune cell around the site of infection (c). iNKT cells are essential for the expression of CXCL10, an inflammatory chemokine, which recruits iNKT cells and initiates granuloma formation (d). Similarly, altogether recruited cells secrete chemokines that attract lymphoid cells, contributing to immune defence against Leishmania parasites. Hepatic CD4⁺ and CD8⁺ T cells are crucial in the liver immune response against leishmaniasis by the formation of granuloma around the site of infection (e). [CCL3: chemokine ligand 3; CCL2: chemokine ligand 2; CXCL10: C-X-C motif chemokine ligand 10; CCR: beta-chemokine receptors; iNKT: invariant natural killer T cells].