Essential Role of Extrathymic T Cells in Protection Against Malaria

Abstract

Athymic nude mice carry neither conventional T cells nor NKT cells of thymic origin. However, NK1.1−TCRint cells are present in the liver and other immune organs of athymic mice, because these lymphocyte subsets are truly of extrathymic origin. In this study, we examined whether extrathymic T cells had the capability to protect mice from malarial infection. Although B6-nu/nu mice were more sensitive to malaria than control B6 mice, these athymic mice were able to survive malaria when a reduced number of parasitized erythrocytes (5 × 103 per mouse) were injected. At the fulminant stage, lymphocytosis occurred in the liver and the major expanding lymphocytes were NK1.1−TCRint cells (IL-2Rβ+TCRαβ+). Unconventional CD8+ NKT cells (Vα14−) also appeared. Similar to the case of B6 mice, autoantibodies (IgM type) against denatured DNA appeared during malarial infection. Immune lymphocytes isolated from the liver of athymic mice which had recovered from malaria were capable of protecting irradiated euthymic and athymic mice from malaria when cell transfer experiments were conducted. In conjunction with the previous results in euthymic mice, the present results in athymic mice suggest that the major lymphocyte subsets associated with protection against malaria might be extrathymic T cells.

Protection against malaria by anti‐erythropoietin antibody due to suppression of erythropoiesis in the liver and at other sites

“…[5][6][7][8][9] Our previous [1][2][3] and present data support these findings. In the case of human malaria, CD36 antigens (sequestrin) on erythrocytes are known to mediate adherence and subsequent infection of Plasmodium falciparum.…”

“…12 The present results remind us of previous data indicating that a major factor involved in malarial protection might be innate immunity mediated by extrathymic T cells in the liver (TCRint cells). [1][2][3][13][14][15] Nucleated erythrocytes infected with malarial parasites still express MHC antigens on their cell surface. 2 Certain autoantigens or malarial antigens inserted into MHC might be recognized by TCRint on extrathymic T cells, and such interaction would induce innate immunity.…”

“…In a series of recent studies, [1][2][3] we observed that erythropoiesis commences in the liver and spleen of mice infected with malaria and that newly generated erythrocytes in the liver become good targets for malarial parasite infection. Nucleated erythrocytes (reticulocytes), rather than mature denucleated erythrocytes (conventional erythrocytes) become the target of malarial parasites.…”

Macrophage-Mediated but Gamma Interferon-Independent Innate Immune Responses Control the Primary Wave ofPlasmodium yoeliiParasitemia

“…The observation that primary peak parasitemia in T-celldeficient mice tends to be comparable to or lower than that of wild-type (WT) mice (10,27,42) is consistent with exacerbation of NK cell function in the absence of T cells, perhaps reflecting compensation for lack of T-and B-cell-mediated effector mechanisms and lack of homeostatic control from regulatory T cells (13,32). Exacerbation of innate immune responses in T-cell-deficient mice limits their utility for assessing the natural role of innate immune mechanisms; furthermore, studies in T-cell-deficient mice cannot address the possibility that induction of Th2 or regulatory T-cell responses, rather than lack of protective Th1 responses, may prevent control of virulent malaria infections.…”

“…ϩ ␣␤ ϩ T cells are critically required for effective clearance of parasitized red blood cells (pRBC), as evidenced by impaired parasite clearance leading to chronic infection and, ultimately, death among athymic and T-cell-deficient mice during infection with a number of malaria parasite species and strains (1,5,24,27,43,61). Moreover, adoptive transfer of naïve CD4…”