CD8+ T cells Are Preferentially Activated during Primary Low Dose Leishmania major Infection but Are Completely Dispensable during Secondary Anti-Leishmania Immunity

Abstract

We previously showed that CD8+ T cells are required for optimal primary immunity to low dose Leishmania major infection. However, it is not known whether immunity induced by low dose infection is durable and whether CD8+ T cells contribute to secondary immunity following recovery from low dose infection. Here, we compared primary and secondary immunity to low and high dose L. major infections and assessed the influence of infectious dose on the quality and magnitude of secondary anti-Leishmania immunity. In addition, we investigated the contribution of CD8+ T cells in secondary anti-Leishmania immunity following recovery from low and high dose infections. We found that the early immune response to low and high dose infections were strikingly different: while low dose infection preferentially induced proliferation and effector cytokine production by CD8+ T cells, high dose infection predominantly induced proliferation and cytokine production by CD4+ T cells. This differential activation of CD4+ and CD8+ T cells by high and low dose infections respectively, was imprinted during in vitro and in vivo recall responses in healed mice. Both low and high dose-infected mice displayed strong infection-induced immunity and were protected against secondary L. major challenge. While depletion of CD4+ cells in mice that healed low and high dose infections abolished resistance to secondary challenge, depletion of CD8+ cells had no effect. Collectively, our results show that although CD8+ T cells are preferentially activated and may contribute to optimal primary anti-Leishmania immunity following low dose infection, they are completely dispensable during secondary immunity.

Assessment of Protection Induced by DNA and Live Vaccine Encoding Leishmania MHC Class I Restricted Epitopes against L. major Challenge in Balb/c Mice Model

“…Both regimens induced partial protection in Balb/c model further potentiating the CD8 + T-cells' role in primary CL infection control. These results are in concordance with a premise postulated by Uzonna et al that stimulation of CD8 + T-cells early after infection is so critical for immune deviation toward Th1 response [19,20]. In our study protection was clearly compromised by CD8 + T-cell depletion at the time of infectious challenge resulting in long lasting Th2 responses.…”

“…CD8 + T-cells depletion at primary infection abolished resistance in C57BL/6 mice infected intra-dermally by 100-1000 metacyclic promastigotes (approximation of low dose natural infection) [33]. Uzonna et al further elucidated that IFN-γ secreted by CD8 + T-cells is important to direct early Th2 type responses towards Th1 and establish protection which will end in a long term memory protecting against subsequent infections [19,20].…”

Cutaneous Infection with Leishmania major Mediates Heterologous Protection against Visceral Infection with Leishmania infantum

“…While Th1 CD4 + T cells are associated with mediating protection against primary and secondary infection with L. major (35, 38), the role of CD8 + T cells in Leishmaniasis remains controversial and is dependent upon the dose, strain, and infection setting (primary or secondary) (1, 38-41). In visceral infection with L. donovani , CD8 + T cells have been shown to be both protective and dispensable (40, 42).…”

Differential Recruitment of Dendritic Cells Subsets to Lymph Nodes Correlates with a Protective or Permissive T-Cell Response duringLeishmania(Viannia)BraziliensisorLeishmania(Leishmania)AmazonensisInfection

“…With regard to the role of CD8 + T-cells, it should be highlighted that these cells have been associated with healing and protection in human and murine leishmaniasis and that their activation is dependent on CD4 + T-cells and DC cells [ 23 – 26 ]. Our results showed that the participation of CD8 + T-cells in the DLN was less evident than the involvement of CD4 + T-cells during infection with both species of the parasite.…”