No abstract

Experimental murine infection with the parasites that cause human visceral leishmaniasis (VL) results in the establishment of infection in the liver, spleen, and bone marrow. In most strains of mice, parasites are eventually cleared from the liver, and hepatic resistance to infection results from a coordinated host response involving a broad range of effector and regulatory pathways targeted within defined tissue structures called granulomas. In contrast, parasites persist in the spleen and bone marrow by mechanisms that are less well understood. Parasite persistence is accompanied by the failure of granuloma formation and by a variety of pathologic changes, including splenomegaly, disruption of lymphoid tissue microarchitecture, and enhanced hematopoietic activity. Here, we review the salient features of these distinct tissue responses and highlight the varied roles that cytokines of the tumor necrosis factor family play in immunity to this infection. In addition, we also discuss recent studies aimed at understanding how splenomegaly affects the survival and function of memory cells specific for heterologous antigens, an issue of considerable importance for our understanding of the disease-associated increase in secondary infections characteristic of human VL.

T lymphocytes lacking the lymph node-homing receptors L-selectin and CCR7 do not migrate to lymph nodes in the steady state. Instead, we found here that lymph nodes draining sites of mature dendritic cells or adjuvant inoculation recruited L-selectin-negative CCR7- effector and memory CD8+ T cells. This recruitment required CXCR3 expression on T cells and occurred through high endothelial venules in concert with lumenal expression of the CXCR3 ligand CXCL9. In reactive lymph nodes, recruited T cells established stable interactions with and killed antigen-bearing dendritic cells, limiting the ability of these dendritic cells to activate naive CD4+ and CD8+ T cells. The inducible recruitment of blood-borne effector and memory T cells to lymph nodes may represent a mechanism for terminating primary and limiting secondary immune responses.

CD8+ T cells have a protective role in experimental visceral leishmaniasis. However, the observation that inflammatory cytokines induce bystander activation of CD8+ T cells questions the need for antigen-dependent effector function. Here, we demonstrate that successful adoptive immunotherapy with CD8+ T cells is strictly dependent upon the presence of cognate antigen.

Little is currently understood about the consequences of chronic parasitic infection for the fate of memory CD4 + T cells that recognize heterologous antigens, e.g. resulting from prior infections or vaccination. Here, we address how Leishmania donovani infection affected the fate of non-cross-reactive (OVA)-specific memory CD4 + T cells. DO11 cells were adoptively transferred into naive recipient mice, which were then immunized to generate memory DO11 cells. After 6 weeks, mice were infected with L. donovani and the fate of DO11 cells was determined. L. donovani infection stimulated an approximately threefold expansion in the total number of CD4 + T cells and DO11 cells, compared to that observed in uninfected mice. DO11 T cells were more actively dividing in infected mice, as judged by 5-bromo-2 0 deoxyuridine labeling, whereas their rate of apoptosis in control and infected mice was identical. Both CD45RB hi CD44 lo naive T cells and to a greater extent CD45RB lo CD44 hi memory DO11 cells increased in number in the spleens of infected mice, whereas no changes occurred to DO11 cell number or phenotype in the draining lymph nodes. These data indicate that heterologous CD4 + T cells may actively divide during chronic infectious diseases, with important implications for how chronic infection may impact on heterologous immunity. IntroductionThe generation of memory T cells with enhanced capacity to respond to subsequent antigen exposure is a fundamental tenet of the acquired immune response, underlying host protection associated with cure from primary infection or resulting from vaccination [1]. Nevertheless, the requirements for the maintenance of immunological memory, notably within the CD4 + T cell compartment, remain to be fully elucidated. Of particular scientific as well as practical relevance is the requirement for the maintenance of a source of cognate antigen in the long-term survival of memory T cells. While it has been established that CD8 + T cell memory may be maintained in the complete absence of antigen [2,3], fewer studies have addressed the need for cognate antigen in the maintenance of CD4 + T cell memory. CD4 + memory T cells have been shown to survive long term in the complete absence of antigen [4] or the ability to present it via MHC II [5,6], at least under conditions where competition from other T cells was minimal. However, such situations may have limited physiological importance. In a contrasting study, intermittent stimulation by persisting antigen was shown to be necessary for CD4 + memory T cell survival [7], although again competition from other T cells was not taken into account.In addition to the possible role of antigen in maintaining CD4 + T cell memory, a number of studies have suggested that the memory T cell compartment itself is of finite size, opening the way for inter-clonal competition for space within this compartment [2,8].The generalization of these observations has, however, yet to be demonstrated, and most models of clonal attrition involve viral or bacterial infectio...

It has been proposed that long-lived memory T cells generated by vaccination or infection reside within a memory compartment that has a finite size. Consequently, in a variety of acute infection models interclonal competition has been shown to lead to attrition of preexisting memory CD8 ؉ T cells. Contrary to expectations, therefore, we found that chronic Leishmania donovani infection of Listeria-immune mice results in heightened protection against subsequent Listeria challenge. This protection was associated with bystander expansion of Listeria-specific CD8؉ T cells and a bias in these cells toward a central memory T-cell phenotype with an enhanced capacity for gamma interferon production. We propose that splenomegaly, which is characteristic of visceral leishmaniasis and other tropical infections, may help promote heterologous immunity by resetting the size of the memory compartment during chronic infection. Memory CD8ϩ -T-cell responses play an essential role in mediating natural and vaccine-induced immunity to a range of important human pathogens, and the dynamics of the CD8 ϩ -T-cell response to a number of prototypic microbial infections has been extensively studied. Activation of naïve CD8 ϩ T cells results in rapid and extensive clonal expansion, followed by a clonal contraction phase. Subsequently, memory CD8 ϩ T cells persist at a higher frequency than their naïve precursors (at approximately 5% of the maximal clone size) and occupy space in a finite memory compartment (1, 7). The mechanisms regulating memory cell persistence in this memory compartment are varied. For example, whereas cross-reactivity can promote the survival of preexisting memory CD8 ϩ T cells (18)(19)(20)22), clonal competition in the absence of cross-reactivity can promote attrition of preexisting memory CD8 ϩ T cells (4,19). In addition, inflammatory cytokines are also thought to play an important role in regulating memory CD8 ϩ -T-cell persistence (21). In the latter case, recent mathematical modeling suggests that clonal contraction should occur rapidly to maintain homeostasis (1).In contrast to these studies with acute infection models, memory cell behavior during chronic infection is less well understood. A recent study demonstrated that in contrast to mice with acute lymphocytic choriomeningitis virus infection, mice with a chronic infection do not develop memory CD8 ϩ T cells with the capacity for long-term antigen-independent persistence. Memory CD8 ϩ cells in these mice exhibit reduced expression of interleukin-7 (IL-7) and IL-15 receptors and fail to undergo homeostatic proliferation (24). However, the impact of chronic infection on the persistence of preexisting hostprotective memory CD8 ϩ T cells has not been described previously. Here, we demonstrate that Leishmania donovani infection of Listeria-immune mice results in significantly enhanced protection against lethal challenge and long-term bystander expansion of Listeria-specific memory CD8 ϩ T cells. We propose that infection-associated splenomegaly may reset the size...