Analysis of the decision criterion controlling the TH1/TH2 nature of a primary immune response
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In this thesis, experiments were undertaken to analyze the cellular mechanisms controlling the differentiation of naive CD4+ T cells to functionally distinct Th1 or Th2 type cells, by employing in vivo and adoptive transfer systems. Immune responses were analyzed by enumerating ex vivo single IgM and IgG-forming B cells and IFNã- and IL-4-producing T cells, employing a plaque assay and a modified ELISPOT assay, respectively. I find that: The Th1/Th2 nature of the splenic immune response of normal mice, immunized intravenously, is determined by the dose of xenogeneic red blood cells (XRBC) used for immunization. Low doses induce an exclusive Th1 response, whereas higher doses induce either a mixed Th1/Th2 or a predominant Th2 type response and stimulate the production of specific antibodies. The Th1/Th2 nature of the response generated in the spleens of irradiated mice depends conjointly on the amount of immunizing antigen and the number of unprimed syngeneic CD4+ T cells employed for reconstitution. Higher amounts of antigen and higher numbers of CD4+ T cells favoring the generation of Th2 type cells. Lowering either the antigen dose or the number of unprimed CD4+ T cells or both, but not the number of antigen-presenting cells favors the exclusive generation of Th1 type cells. Thus, more CD4+ T cell/CD4+T cell interactions is required for the primary generation of Th2 than Th1 type cells. The Th1/Th2 nature of the response is determined by CD4+ T cell/CD4+ T cell interactions mediated by operational linked recognition of antigenic epitopes. Immunization of C57BL/6 hen egg lyzozyme (HEL)-transgenic mice, tolerant to HEL, and their wild type counterparts with low doses of sheep RBC, generates predominantly a SRBC-specific Th1 type response in both mice. In contrast, immunization with a low dose of SRBC physically coupled to HEL results in a modulation of the anti-SRBC response from a Th1 to Th2 mode, in normal C57BL/6 mice but not in the HEL-transgenic mice. Such modulation requires that HEL physically linked to SRBC and not to other non-crossreacting antigen. The Th1/Th2 nature of concurrent immune responses, generated in the same secondary lymphoid organ upon immunization with two non-crossreacting antigens, can be independently determined. Thus, the Th1/Th2 nature of the response to two XRBC, given in different doses, in doubly immunized mice was indistinguishable from that of the corresponding immune response in singly immunized mice. Furthermore, the Th1/Th2 response to one kind of XRBC is independent of ongoing immune responses to another noncrossreacting RBC.