55 research outputs found
Tolerance to Self: Which Cells Kill
Immune self tolerance involves the deletion in the thymus of developing T cells that have the ability to recognize self-antigens, but by which cells? New evidence argues that cortical epithelial cells can induce deletion of self-reactive T cells
MHC Class II Expression Restricted to CD8Ī±+ and CD11b+ Dendritic Cells Is Sufficient for Control of Leishmania major
Control of the intracellular protozoan, Leishmania major, requires major histocompatibility complex class II (MHC II)ādependent antigen presentation and CD4+ T cell T helper cell 1 (Th1) differentiation. MHC IIāpositive macrophages are a primary target of infection and a crucial effector cell controlling parasite growth, yet their function as antigen-presenting cells remains controversial. Similarly, infected Langerhans cells (LCs) can prime interferon (IFN)Ī³āproducing Th1 CD4+ T cells, but whether they are required for Th1 responses is unknown. We explored the antigen-presenting cell requirement during primary L. major infection using a mouse model in which MHC II, I-AĪ²b, expression is restricted to CD11b+ and CD8Ī±+ dendritic cells (DCs). Importantly, B cells, macrophages, and LCs are all MHC IIānegative in these mice. We demonstrate that antigen presentation by these DC subsets is sufficient to control a subcutaneous L. major infection. CD4+ T cells undergo complete Th1 differentiation with parasite-specific secretion of IFNĪ³. Macrophages produce inducible nitric oxide synthase, accumulate at infected sites, and control parasite numbers in the absence of MHC II expression. Therefore, CD11b+ and CD8Ī±+ DCs are not only key initiators of the primary response but also provide all the necessary cognate interactions for CD4+ T cell Th1 effectors to control this protozoan infection
Ezrin Is Highly Expressed in Early Thymocytes, but Dispensable for T Cell Development in Mice
Ezrin/radixin/moesin (ERM) proteins are highly homologous proteins that function to link cargo molecules to the actin cytoskeleton. Ezrin and moesin are both expressed in mature lymphocytes, where they play overlapping roles in cell signaling and polarity, but their role in lymphoid development has not been explored.We characterized ERM protein expression in lymphoid tissues and analyzed the requirement for ezrin expression in lymphoid development. In wildtype mice, we found that most cells in the spleen and thymus express both ezrin and moesin, but little radixin. ERM protein expression in the thymus was differentially regulated, such that ezrin expression was highest in immature thymocytes and diminished during T cell development. In contrast, moesin expression was low in early thymocytes and upregulated during T cell development. Mice bearing a germline deletion of ezrin exhibited profound defects in the size and cellularity of the spleen and thymus, abnormal thymic architecture, diminished hematopoiesis, and increased proportions of granulocytic precursors. Further analysis using fetal liver chimeras and thymic transplants showed that ezrin expression is dispensable in hematopoietic and stromal lineages, and that most of the defects in lymphoid development in ezrin(-/-) mice likely arise as a consequence of nutritional stress.We conclude that despite high expression in lymphoid precursor cells, ezrin is dispensable for lymphoid development, most likely due to redundancy with moesin
Treating MS: getting to know the two birds in the bush
Current therapies for immune-mediated diseases, such as rheumatoid arthritis and MS,
could represent the proverbial bird in the hand ā a known entity, yet
limited in potential. Emerging biologic therapeutics for these diseases carry with
them the potential for known as well as unknown adverse effects. Alemtuzumab, a
biologic that depletes leukocytes, shows great promise for the treatment of MS.
However, a significant number of patients develop autoimmunity after treatment,
raising the level of caution for the use of this drug. In this issue of the
JCI, Jones et al. describe a link between IL-21 levels and
alemtuzumab-associated autoimmunity (see the related article beginning on page 2052).
They show that proliferation of lymphocytes in those patients with autoimmunity is
higher than in those without autoimmunity and suggest that the lymphopenia-driven
proliferation of T cells, in combination with higher IL-21 levels, results in
autoimmunity. This study helps inspire new enthusiasm for making a grab for the
proverbial two birds in the bush ā representing undiscovered therapies
ā with greater confidence
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