Chronic Leishmania donovani Infection Promotes Bystander CD8 ⁺ -T-Cell Expansion and Heterologous Immunity

Abstract

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...

Bystander T cell activation – implications for HIV infection and other diseases

“…One theory is that bystander activation following infection might simply be a homeostatically induced proliferation following the T-cell depletion characteristic of some infections. Alternatively, infection could induce splenomegaly, creating more space for heterologous memory cells [15]. Indeed some of the characteristics seem similar, yet the experiments of Gilbertson et al [16], performed in mice infected with Mycobacterium avium (which naturally induces T-cell depletion), indicate that bystander activation and homeostatic proliferation are similar but distinct processes.…”

Heterologous immunity between viruses

“…There is always a question of how much of heterologous immunity is mediated exclusively by cross‐reactive mechanisms and how much by non‐specific bystander mechanisms, and this remains an issue even when cross‐reactive epitopes can be found (). Several studies have concluded that memory T cells can be subjected to bystander activation by cytokines independent of TCR signaling and that these non‐specifically activated cells may contribute to heterologous immunity (15, 102–104). It has also been reported that IL‐12 and IL‐18 can non‐specifically stimulate the production of IFNγ by memory T cells (16), and VV infection will induce the synthesis of IL‐12 in mice (6).…”

Chronic Bystander Infections and Immunity to Unrelated Antigens

“…GB virus C can inhibit HIV replication and HIV-infected individuals that are co-infected with GB virus C have an almost four-fold reduced rate of mortality (Xiang et al, 2001). Similarly, mice chronically infected with the protozoan parasite Leishmania were protected against subsequent bacterial challenge, potentially due to the induced splenomegaly and expansion of CD8 T cells (Polley et al, 2005). …”