The peripheral T cell compartment is made up of naive lymphocytes with a diverse T cell receptor repertoire and activated/memory lymphocytes specifically recognizing antigens encountered during the lifetime of the host. Because this dichotomy is maintained mainly by egress of naive T lymphocytes generated in thymus and by post-thymic differentiation of activated/memory T cells, it is generally accepted that the two pools are independently regulated. However, we have observed that systemic infection with the protozoan parasite Toxoplasma gondii in addition to leading to an increase in activated CD4+ Th1 cells also triggers a decrease in the size of the naive CD4+ T lymphocyte population. This profound alteration is caused primarily by parasite-induced destruction of the thymic epithelium in addition to glucocorticoid-mediated thymocyte depletion. Importantly,as demonstrated in experiments performed during the report period, the resulting deficiency in nave CD4 T cells leads to an immunocompromised state in which animals chronically infected with T. gondii are susceptible to challenge with an unrelated pathogen while maintaining control of the primary infection itself. This long-term immunological alteration is an unexpected negative consequence of chronic systemic infection and mirrors many of the changes associated with aging of the immune system. The NOD receptors are cytoplasmic pattern recognition receptors previously characterized as recognizing bacterial cell wall peptidoglycans. Unexpectedly, when infected i.p. with T. gondii NOD1, but not NOD2, deficient mice display rapid mortality. The uncontrolled parasitemia in NOD1KO mice was a consequence of defective adaptive rather innate immunity and was accompanied by a systemic decrease in the number of lymphocytes. Subsequent analyses revealed that uninfected NOD1-/- animals display smaller lymphoid organs and reduced number of T and B lymphocytes. To determine whether NOD1 expression in hematopoietic cells is critical for the generation of lymphocytes, we generated chimeric mice by reconstituting irradiated WT mice with BM from WT and NOD1-/- animals (1:1). We found that NOD1-/- lymphocytes contribute less than 5% of the total lymphocytes in peripheral tissues of the recipient mice. Detailed comparison of the bone marrow (BM) of these animals showed that when compared with WT mice, NOD1-/- animals display a selective decrease in the number of multipotent progenitors (MPP) and common lymphoid progenitors (CLP). Interestingly, we observed that germ-free mice display a similar reduction in the number of MPP and CLP, a finding that shows that the gut microbiota can affect the pool of the major hematopoietic precursors in BM. Importantly, oral administration of NOD1 ligand to germ free animals restored the number of MPP and CLP to the same level as in SPF mice. These findings strongly suggest that NOD1 signaling is required for optimal development of lymphoid progenitors in BM at steady state, a function that becomes particularly prominent under conditions of immune stress induced by infection. Studies in the mouse, a natural host of T. gondii, have shown that the innate immune response depends on the expression of two MyD88-dependent pattern-recognition receptors, TLR11 and TLR12 on dendritic cells. Thus, mice deficient in MyD88 or TLR11/12 rapidly succumb to acute infection due to uncontrolled parasitemia. The ligand for TLR11/12, which is present in soluble parasite extracts, was determined to be a profilin-like protein. While these findings highlighted a critical role for the innate recognition of toxoplasma, they also revealed a major gap in translation to clinical T.gondii infection since humans do not express either TLR11 or TLR12. In order to address how human innate immune cells detect and respond to T. gondii, we infected primary human monocytes and monocyte-derived dendritic cells with T. gondii and found that upon infection both cell types produce significant levels of TNF-alpha and p40 IL-12. In direct contrast to murine innate cells, human monocytes and dendritic cells did not respond to soluble toxoplasma extracts or killed parasites. Although uptake of live parasites was required for an optimal response in human monocytes, we demonstrated that active parasite invasion was dispensable for cytokine production which instead depends on parasite phagocytosis. Interestingly, CD16+ but not CD16- monocytes were capable of producing TNF and IL-12 in response to T.gondii exposure. Taken together, our results establish that human CD16+ monocytes (as well as dendritic cells) are triggered by T.gondii via an innate recognition pathway that is distinct from that previously characterized by us in murine dendritic cells.
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