The differentiation of effector Th cell is separated into three general types according to the lymphokines produced and the effector immune response elicited (Table 2). The DTH-mediating effector T cells are the type 1 Th (Th1) cells. Th1 cells are characterized by their secretion of interferon-y (INF-y) and tumor necrosis factor (TNF). The type 2 Th (Th2) cells mediate B-cell growth and allergic immune responses. The characteristic lymphokines produced by Th2 cells are IL-4 and IL-10. A third type of Th (Th3) cell has only recently been characterized. They are the result of oral tolerance and possibly the effect of aqueous humor (fluid from the anterior chamber of the eye) factors on activated T cells. These Th3 cells produce transforming growth factor-P (TGF-P) and IL-4 or IL-10. They have the ability to suppress autoimmune diseases mediated by Th1 cells with a potential to also suppress Th2-mediated responses. The path of differentiation by the activated T cells is associated with the manner that antigen is presented, with the type of APC, and the elements within the microenvironment where the T cells are activated. It is also at this level that the innate immune response can influence the induction of adaptive immunity.
The intracellular signals that emanate from the TCR regulate T-cell proliferation, lymphokine production, and expression of surface receptors. The affinity between the TCR and processed antigen-
bound MHC regulates the intensity and fidelity of tyrosine phosphorylation of CD3 proteins, TCR-asso-ciated molecules. Changes in the affinity due to amino acid substitution of the processed antigen or to presentation of antigen by unfavorable MHC binding mediate differential TCR signals within activated T cells. High-affinity binding of TCR to antigen presented MHC leads to induction of Th1 responses, whereas low-affinity binding leads to Th2 responses and possibly Th3 development.
Presentation of antigen by macrophages and dendritic cells usually leads to inducing Th1 cells. This may be due to the role of macrophages and dendritic cells in innate immunity. Potential pathogens express pathogen-associated molecular patterns (PAMP), which are molecules that are intrinsic to the pathogen's structure or are necessary for its survival. The PAMP induce IFN-y, IL-12, and TNF production, antigen processing, and class II MHC expression on macrophages and dendritic cells. Such activated macrophages and dendritic cells mediate activation of Th1 cells because they can present antigen in a microenvironment rich in Th1 cell growth factors (IFN-y, and IL-12). On the other hand, B cells when activated by binding antigen to their surface immunoglobulin, process the internalized antigen and present it on class
11 MHC to T cells in a manner the promotes Th2 development. This promotion of Th2 responses has been speculated to be caused by B cell over expression of accessory activating protein B7.2 and production of IL-1. Another possibility has been suggested that Th2 development is a default T-cell differentiation pathway. Activation of Th cells in the absence of IL-
12 and IFN-y leads to development of Th2 cells; however, this is some what questionable because there exist strains of mice that appear to default to Th1.
The innate immune response to PAMP is not limited to inducing a Th1-mediated adaptive immune response. Activation of NKT cells mediates induction of Th2 cells. These NKT cells respond to antigen presented in the cleft of CD1, a MHC class-I like molecule expressed on cells such as intestinal epithelial cells, and secrete IL-4 influencing development of Th2 cells. Other cells that can influence the Th cell activation microenvironment are natural killer (NK) cells that secrete IFN-y when activated by cells not expressing MHC class I. Under these conditions NK cells promote development of Th1 cells. Microenvironments rich in TGF-P, such as the anterior chamber of the eye, have the potential to promote development of Th3 cells. In addition, lymphokines produced by activated T cells can also influence the differentia tion of other activated T cells. The lymphokines IFN-y and IL-4 both suppress the production of each other and thus promote development of Th1 cells or Th2 cells, respectively. Activated Th3 cells through TGF-P, with IL-4 or IL-10 production, can suppress the activation and possibly the development of both Th1 and Th2 cells.
Since Th cell activation and differentiation is a coordinated sequence of antigen recognition, accessory protein binding, and cytokine activity, it can be regulated at the level of antigen presentation and by the microenvironment in which the Th cells are activated. It is considered that within immune privileged sites such as the eye and brain the parenchymal cells that make up the microenvironment contribute factors that locally regulate immune responses. More conventional tissues sites such as the skin use similar regulatory mechanisms as immune privileged sites in a limited manner to maintain immune homeostasis.
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