Memory T cells: promising biomarkers for evaluating protection and vaccine efficacy against leishmaniasis

Abstract

Understanding the immune response to Leishmania infection and identifying biomarkers that correlate with protection are crucial for developing effective vaccines. One intriguing aspect of Leishmania infection is the persistence of parasites, even after apparent lesion healing. Various host cells, including dendritic cells, fibroblasts, and Langerhans cells, may serve as safe sites for latent infection. Memory T cells, especially tissue-resident memory T cells (T_RM), play a crucial role in concomitant immunity against cutaneous Leishmania infections. These T_RM cells are long-lasting and can protect against reinfection in the absence of persistent parasites. CD4⁺ T_RM cells, in particular, have been implicated in protection against Leishmania infections. These cells are characterized by their ability to reside in the skin and rapidly respond to secondary infections by producing cytokines such as IFN-γ, which activates macrophages to kill parasites. The induction of CD4⁺ T_RM cells has shown promise in experimental immunization, leading to protection against Leishmania challenge infections. Identifying biomarkers of protection is a critical step in vaccine development and CD4⁺ T_RM cells hold potential as biomarkers, as their presence and functions may correlate with protection. While recent studies have shown that Leishmania-specific memory CD4⁺ T-cell subsets are present in individuals with a history of cutaneous leishmaniasis, further studies are needed to characterize CD4⁺ T_RM cell populations. Overall, this review highlights the importance of memory T cells, particularly skin-resident CD4⁺ T_RM cells, as promising targets for developing effective vaccines against leishmaniasis and as biomarkers of immune protection to assess the efficacy of candidate vaccines against human leishmaniasis.

Keywords: biomarkers; leishmaniasis; memory CD4+ T cells; tissue resident memory; vaccine.

Figure 1

The development of T cells and their contribution in the immunity during experimental cutaneous Leishmania infection. At the site of sand fly bite, Leishmania metacyclic promastigotes infect cells of the monocyte–macrophage lineage including macrophages and DCs in the skin dermal layer. Within the host cells, promastigotes transform to the amastigote stage and replicate by binary fission (1). Infected antigen-presenting cells (APCs) carry antigens to lymphoid organs leading to activation of CD4⁺ T cells in the draining lymph nodes (2). Activated CD4⁺ T cells in the draining lymph nodes could develop into either effector T (T_EFF) cells or central memory T (T_CM) cells. In the course of secondary infection, the residing T_CM cells could be reactivated and differentiated into different subsets of CD4⁺ T_EFF cells (3) that provide a circulating pool of Leishmania-reactive T cells (4). Circulating CD4⁺ T_EFF cells can be rapidly recruited into the site of infection, while some T_EFF cells may migrate into skin distant from the lesion site and become resident memory T (T_RM) cells (5). In response to challenge, T_RM cells in the skin produce cytokines that mediate recruitment of inflammatory monocytes and effector T cells from the blood (6).

Figure 2

Differential phenotypes of mouse and human resident memory (T_RM) cells. T_RM cells are identified by the expression of canonical receptors CD103 and CD69, as well as several other surface markers depending on the specific resident tissues. T_RM cells display upregulation of the expression of some transcriptional factors, including Hobit, Blimp1, Runx3, and Notch (/RBPj).

Figure 3

Factors involved in the development of Leishmaniasis vaccines aimed at inducing skin-resident memory T cell response. Effective vaccine strategies for inducing T_RM cell responses in leishmaniasis will rely on a comprehensive understanding of the development and maintenance of protective T_RM cells in Leishmania infection. Exploring the potential migration and localization of vaccine-induced T_RM cells in specific sites in the skin and the signals needed to activate efficient T_RM cells in an interactive microenvironment with other immune cells is also imperative. Various other factors of Leishmania parasite, host background, and vaccine design are involved in the effectiveness of candidate vaccines targeting the generation of protective T_RM cells.