Lymphocyte costimulatory molecules

In the specialized environment of secondary lymphoid tissues such as lymph nodes or spleen, dendritic cells provide the requirements for naive T-lymphocytes to become activated and to proliferate. The professional antigen-presenting cells present peptides in MHC II, express costimulatory molecules, and release cytokines into the immunological synapse, which is formed by the antigen-presenting cell and the naive T-lymphocyte. Thus, cells of innate immunity initiate and facilitate the activation of naive lymphocytes, and it is easily conceivable that their cytokines and adhesion molecules will instruct the naive T-lymphocyte during activation and differentiation to T-effector cells. 

In addition to its classical role as regulator of calcium homeostasis, 1,25-dihydroxy vitamin D3 (calcitriol) displays immunosuppressive properties. Inhibition of T-lymphocyte proliferation seems to be mediated via regulation of CD80/86 costimulatory molecule expression on APCs. For clinical use as immunosuppressant, however, analogues of vitamin D3 that do not influence calcium metabolism are needed. 

IFN-y also induces the costimulatory molecules on the macrophages, which increases cell-mediated immunity. As a consequence, there is activation and increase in the tumoricidal and antimicrobial activity of mononuclear phagocytes, granulocytes and NK cells. The activation of neutrophils by IFN-y includes an increase in their respiratory burst. IFN-y stimulates the cytolytic activity of NK cells. It is an activator of vascular endothelial cells, promoting CD4+ T lymphocyte adhesion and morphological alterations, which facilitates lymphocyte extravasation. IFN-y promotes opsonization by stimulating the production of IgG subclasses that activate the complement pathway. A summary of the characteristics of selected cytokines is shown in Table 2.3. 

Figure 22.2 Cellular activation by CpG DNA. CpG DNA directly activates dendritic cells (DCs), monocytes and macrophages, to express increased levels of co-stimu-latory molecules, to increase antigen presentation, and to secrete high levels of chemokines and cytokines, such as interleukin 12 (IL-12), interferon-a(IFN-a), and tumor necrosis factor-a (TNF-a), and monocytes and macro-phages have increased antibody-dependent cellular cytotoxicity (ADCC) activity. NK cells are induced to express IFN-7 by these cytokines acting in concert with CpG, and have increased lytic activity. B cells rapidly produce IL-b and IL-10 and express increased levels of costimulatory molecules. B cells rapidly enter the cell cycle and become resistant to some forms of activation-induced cell death. T cells are not directly activated by CpG, but because of the T helper 1 (Thl)-like cytokine environment, and the increased antigen presenting cell (APC) activity, antigen-specific Thl cells and cytotoxic T lymphocytes (CTL) are generated.

T lymphocytes are called the conductors of the immunological orchestra. Twenty years ago Th and Ts lymphocytes were described, and then based on the released cytokines within the Th type, Thl was determined, which releases IFNy and a lym-photoxin, and Th2, which releases IL 4, IL 5, IL 10, and IL 13. Soon it became evident that there was a third subpopulation of lymphocytes—Thl7—involved in infectious immunity and autoimmunological processes. T lymphocytes need to be presented with an antigen in order to activate their functions. Therefore, it seems that the character and volume of stimulation are determined by the type and dose of an antigen, the mode of presentation in terms of costimulatory molecules, and finally the concentration and content of cytokines contained in stroma, as well as the stage in mechanism processes. 

In order to stimulate the transformation of lymphocytes, another signal is needed, which will be delivered from the interaction between costimulatory molecules on the surface of DCs and CD40, which is a ligand. Examples for costimulatory... 

T-cell activation is caused by interactions between T-cell receptors, the MHC, cellular adhesion molecues, and costimulatory molecules. Among the series of events is calcineurin activation, which ultimately promotes interleukin 2 (IL-2) proliferation. After initial T-cell activation, the process of clonal expansion and immunologic progression is mediated by cytokines. IL-2 is released from T cells and activates T-lymphocytes locally and in other regions of the... 

At least two environmental factors may contribute to the development of HP as a promoting factor viral infections and inhalation injury. Experimental models of HP have shown that animals challenged with respiratory syncytial virus or Sendai virus exhibit a more severe inflammatory response to subsequent Saccharopolyspora rectivirgula exposure, which may persist long after the viral infection has declined (11,12). Also, studies in humans have revealed that common respiratory vimses, primarily Influenza A, are often present in the lower airways of patients with HP (13). The reasons why viral infections may potentiate HP are unknown, but it may be related to vims-induced mucociliary dysfunction, increased expression of costimulatory molecules by alveolar macrophages, and increased secretion of chemokines, enhancing the recruitment of lymphocytes to the lungs (13,14). 

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