CD8+ T Cells Lack Local Signals To Produce IFN-γ in the Skin during Leishmania Infection

Abstract

Resolution of leishmaniasis depends upon parasite control and limiting inflammation. CD4 Th1 cells are required to control parasites, whereas CD8 T cells play a dual role: they promote Th1 cell differentiation but can also increase inflammation at the site of infection as a consequence of cytolysis. Although CD8 T cells taken from leishmanial lesions are cytolytic, in this study, we showed that only a few CD8 T cells produced IFN-γ. Correspondingly, only low levels of IL-12 and/or IL-12 mRNA were present in lesions from infected mice, as well as patients. Addition of IL-12 increased IFN-γ production by CD8 T cells isolated from leishmanial lesions, suggesting that a lack of IL-12 at the site of infection limits IFN-γ production by CD8 T cells. To determine whether CD8 T cells could promote resistance in vivo if IL-12 was present, we administered IL-12 to -infected RAG mice reconstituted with CD8 T cells. IL-12 treatment increased the ability of CD8 T cells to make IFN-γ, but CD8 T cells still failed to control the parasites. Furthermore, despite the ability of CD8 T cells to promote immunity to secondary infections, we also found that CD8 T cells from immune mice were unable to control in RAG mice. Taken together, these results indicate that lesional CD8 T cells fail to make IFN-γ because of a deficit in IL-12 but that, even with IL-12, CD8 T cells are unable to control in the absence of CD4 T cells.

Contribution of Leishmania braziliensis antigen-specific CD4+ T, CD8+ T, NK and CD3+CD56+NKT cells in the immunopathogenesis of cutaneous leishmaniasis patients: Cytotoxic, activation and exhaustion profiles

“…immune response against Leishmania braziliensis, with defined cytokine network, has been exhaustively reported [12][13][14][15][16][17]. Nevertheless, in some situations, a strong inflammatory response contributes to lesion progress and to exacerbation of the disease, which has been associated with cytotoxic events [9][10][11][12][13]. Recently, our group investigated the contributions of cytotoxic CD4 + T, CD8 + T, NK and NKT cells in the immune response in blood from CL patients before, during and after antimonial treatment, highlighting an important cytotoxic activity by CD4 + T and NKT cells, differently from classical-cytotoxic cells, as CD8 + T and NK cells [19].…”

“…Much is discussed about the events associated with the infection and its resolution and it has been suggested that CD4 + T lymphocytes mediate a protective immunity, whereas CD8 + T lymphocytes would have a pathological-cytotoxic role [9][10][11][12][13]. Nevertheless, a protective role for CD8 + T cells in the host immune response has already been clearly established [14][15][16][17][18].…”

The Binomial Parasite-Host Immunity in the Healing Process and in Reactivation of Human Tegumentary Leishmaniasis

“…CD8 + T cells are considered important components of the inflammatory infiltrate present in the lesions ( Faria et al, 2009 ; Santos et al, 2013 ). However, its function has been discussed and recently it has been demonstrated that according to the functional profile, CD8 + T cells could play a beneficial (increasing the supply of IFN-γ) or harmful (by the predominance of cytotoxic activity) role ( Novais and Scott, 2015 ; Novais et al, 2018 ). Neutrophils have also been involved in the decrease in parasite load or in the amplification of macrophage infection ( Tacchini-Cottier et al, 2000 ; John and Hunter, 2008 ; Conceição et al, 2016 ).…”

Post kala-azar dermal leishmaniasis: A threat to elimination program

“…Furthermore, using monoclonal antibody-based approach targeting the immune checkpoint molecules and/or immunoregulatory cytokines can be another avenue that can open possibilities for therapeutic intervention. PKDL infection is associated with lack of IFNγ producing signals in the skin [200] and administration of exogenous recombinant cytokine can potentially alleviate disease pathogenesis. Therefore, immunomodulatory therapy aiming to relieve the immunosuppressive microenvironment and instigate protective Th1 responses can be used together with chemotherapeutic regimens during VL treatment to prevent the emergence of PKDL.…”