Loss of Dendritic Cell Migration and Impaired Resistance toLeishmania donovaniInfection in Mice Deficient in CCL19 and CCL21

Abstract

The encounter between antigen-presenting cells and T cells is crucial for initiating immune responses to infectious microorganisms. In the spleen, interaction between dendritic cells (DC) and T cells occurs in the periarteriolar lymphoid sheath (PALS) into which DC and T cells migrate from the marginal zone (MZ) along chemokine gradients. However, the importance of DC migration from the MZ into the PALS for immune responses and host resistance to microbial infection has not yet been elucidated. Here we report that following Leishmania donovani infection of mice the migration of splenic DC is regulated by the CCR7 ligands CCL19 / CCL21. DC in plt/plt mutant mice which lack these chemokines are less activated and produce less IL-12, compared to those in wild type mice. Similar findings are seen when mice are treated with Pertussis toxin, which blocks chemokine signalling in vivo. plt/plt mice had increased susceptibility to L. donovani infection compared to wild type mice, as determined by spleen and liver parasite burden. Analysis of splenic cytokine profiles at day 14 post infection demonstrated that IFNγ and IL-4 mRNA accumulation was comparable in wild type and plt/plt mice. In contrast, accumulation of mRNA for IL-10 was elevated in plt/plt mice. In addition, plt/plt mice mounted a delayed hepatic granulomatous response and fewer effector T cells migrated into the liver. Taken together, we conclude that DC migration from the MZ to the PALS is necessary for full activation of DC and the optimal induction of protective immunity against L. donovani.

CCR7 Deficiency Leads to Leukocyte Activation and Increased Clearance in Response to Pulmonary Pseudomonas aeruginosa Infection

“…This is in agreement with previous reports that conclude that CCR7 and its ligands are required for the migration of activated dendritic cells from the periphery to the lymph node (10,17,29). However, other studies have investigated additional roles for CCR7 in dendritic cell function other than migration and concluded that CCR7 signaling is critical for full maturation of licensed dendritic cells (1,24). These two studies used plt mice, which are a naturally occurring mutant strain that lack CCL19 and expresses CCL21 only at reduced levels in some peripheral organs.…”

“…CCL19 and CCL21 expression has been identified in peripheral organs, such as the lung (27,43), but their role in host defense is not fully understood. Previous studies employing models of pulmonary infection have shown that CCR7 deficiency leads to impaired host defense (1,6,15,18,19,22,31). However, we demonstrated that CCR7 deficiency FIG.…”

“…Many studies employed viral pathogens (6,15,18,19,31), while other studies investigated infections by Listeria monocytogenes (22) or Leishmania donovani (1). Each of these studies indicated that clearance of infection is delayed or impaired in plt or Ccr7 Ϫ/Ϫ mice.…”

Gamma Interferon-Regulated Chemokines in Leishmania donovani Infection in the Liver

“…We used the responses in the livers of deficient mice to infer nonredundant roles for individual chemokines, and we refer below to the six that we studied as "IFN-␥-regulated chemokines." We understand, however, that IFN-␥ induces other chemokines in the L. donovani-infected liver (Table S2), additional chemokines are active in this model (e.g., CCL3 [40] and CCL19/21 [41]), and chemokines and their receptor ligands have pleiotropic effects beyond mononuclear cell recruitment. The latter include T cell stimulation, cytokine secretion, and direct macrophage activation (15-17, 19, 40-42).…”

Leishmania majorPhosphoglycans Influence the Host Early Immune Response by Modulating Dendritic Cell Functions

“…We previously showed that similar to WT, lpg2 Ϫ L. major parasites can invade macrophages but are progressively destroyed beyond 24 h (45). DCs, which are among the first cells infected by Leishmania (3,40), are the most efficient antigen-presenting cells and hence are essential for inducing an efficient anti-Leishmania adaptive immune response (41). To investigate the possible effect of LPG2-dependent molecules on DC function, we generated BMDCs and determined their expression of costimulatory molecules after infection with WT and lpg2 Ϫ L. major.…”