A Role for Tumor Necrosis Factor-α in Remodeling the Splenic Marginal Zone during Leishmania donovani Infection

Abstract

The development of secondary lymphoid organs is a highly regulated process, mediated by tumor necrosis factor (TNF) family cytokines. In contrast, the mechanisms controlling changes in lymphoid architecture that occur during infectious disease are poorly understood. Here we demonstrate that during infection with Leishmania donovani, the marginal zone of mice undergoes extensive remodeling, similar in extent to developmental abnormalities in mice lacking some TNF family cytokines. This process is selective, comprising a dramatic and rapid loss of marginal zone macrophages (MZMs). As a functional consequence, lymphocyte traffic into the white pulp is impaired during chronic leishmaniasis. Significantly, MZMs were preserved in L. donovani-infected B6.TNF-alpha(-/-) mice or mice that received anti-TNF-alpha antibodies, whereas studies in CD8(+) T-cell-deficient mice and in mice lacking functional CD95L, excluded a direct role for either cytotoxic T lymphocyte activity or CD95-mediated apoptosis in this process. Loss of MZMs was independent of parasite burden, yet could be partially prevented by chemotherapy, which in turn reduced endogenous TNF-alpha levels. This is the first report of an infectious agent causing selective and long-lasting changes to the marginal zone via TNF-alpha-mediated mechanisms, and illustrates that those cytokines involved in establishing lymphoid architecture during development, may also play a role in infection-induced lymphoid tissue remodeling.

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“…This functional role for the FRC network, when taken in conjunction with our prior finding that the FRC network is remodeled during experimental VL (22), is entirely consistent with the observation that T cell migration into the periarteriolar lymphocytic sheath (PALS) is severely impaired in mice with VL (19). Mice with progressive VL also have defective traffic of DCs into the PALS, although this functional defect reflects IL-10-induced inhibition of CCR7 expression, rather than the defective production of CCL21 and CCL19 that occurs as a consequence of loss of the FRC network (22).…”

“…Quantitative analysis demonstrated that there was a significant increase in the frequency of CD31 + vessels with accompanying α-SMA + mesenchymal cells (14 dpi, 32% ± 5% of all CD31 + cells; 28 dpi, 90% ± 4%; Figure 3B). The marginal zone sinus also undergoes some disruption during experimental VL (19). However, we, as well as others working in murine models of malaria (24), noted that MAdCAM-1, the marker usually used to identify marginal sinus lining cells in the spleen, became expressed in a diffuse pattern across the white pulp after infection (Supplemental Figure 1), making it difficult to quantify changes in the marginal sinus with any degree of certainty.…”

“…17); these were conducted in the hope that a greater understanding of the processes involved might shed light on new therapeutic approaches. We have previously shown that progressive infection with L. donovani in mice is characterized by breakdown of splenic marginal zone architecture, with loss of marginal zone macrophages (MZMs) and repositioning of marginal metallophilic macrophages (MMMs) (17)(18)(19)(20). Within the splenic white pulp, there is also disruption to both the follicular DC (FDC) network in B cell follicles (21) and the gp38 + fibroblastic reticular cell (FRC) network that guides T cell and DC migration in the T cell zone (22).…”

The fate of heterologous CD4+ T cells during Leishmania donovani infection

“…Early infection is accompanied by rapid IL-12 production by DC [12], the activation of CD4 + and CD8 + T cells, and the subsequent production of a variety of Th1 and Th2 cytokines, including IL-2, 14]. While this immune response can readily eliminate most L. donovani amastigotes from the liver of infected mice over a 50-100-day period [15], parasites persist in the spleen, and this persistence is associated with severe splenomegaly and an array of pathological changes to the splenic lymphoid microenvironment [16][17][18]. Little is known, however, about T cell dynamics in this highly inflammatory environment, although previous studies have indicated an increase in the rate of apoptotic CD4 + and CD8 + T cells during the later stages of infection [19].…”

“…Alternatively, proliferation of DO11 cells may be triggered by TCR-independent cytokine-mediated mechanisms. TNF-a, IL-2, IL-4 and IFN-c are all upregulated during chronic infection [13,14,18] and have been implicated in antigen-independent proliferation of human [35] and murine [36,37] memory CD4 + T cells. However, the action of bystander cytokines alone is unlikely to explain our data, as such a model would have also predicted the expansion of DO11 cells in L. donovani-infected mice in the absence of OVA, something we have not observed.…”