Specific Immune Responses Of T Cells And B Cells

Synopsis: Specific lymphocyte activation leads to cell cycling (clonal expansion), T cell/B cell-antigen presenting cell interactions, altered cell traffic, and altered expression of many genes in the transplanted organ and elsewhere in the host. The lymphocyte population changes. Many lymphocyte activation events may actually occur within the graft, as opposed to the lymphoid organs.114 Three lines of lymphocyte differentiation lead to effector mechanisms, which require massive clonal expansion to become quantitatively important:

1. The delayed type hypersensitivity response, principally engineered by cytokines from CD4 T cells;

2. The B-cell antibody response, dependent on CD4 T cell help;

3. The cytotoxic T-cell response by CD8 cells.

Activated CD4 cells influence other cells through two mechanisms: the production of cytokines, which interact through their receptors to signal the target cell, and direct interaction through their TCRs and adhesion and signalling molecules. Direct interactions must involve the same MHC plus peptide for which the CD4 T cell is primed. In direct interactions, the release of cytokines is directional, focused on the target by the TCR and the adhesion molecules.134,135 Activated CD4 cells help CD8 cells to become cytotoxic and B cells to make antibody and activate macrophages and endothelial cells to mediate delayed type hypersensitivity.

Division of Labor Among CD4 Cells: "TH1" and "TH2" Cytokines8

The primary function of CD4 T cells is to produce cytokines, which they do more efficiently than CD8 cells. Naive CD4 T cells produce primarily IL-2, with increasing amounts of assorted other cytokines. With prolonged stimulation, e.g., in cloning experiments in vitro and under certain conditions in vivo,136 CD4 T cells cease production of some cytokines and increase production of others in characteristic patterns: a "TH1" pattern or "TH2" pattern. The TH1 pattern of cytokine production is IFN-y, lymphotoxin, and IL-2. The TH2 pattern consists of IL-4, IL-5, IL-6, and IL-10 (Table 1.4). These are called the TH1 and TH2 cytokines respectively. CD4 T cells can be found which produce exclusively TH1 or TH2 cytokines and are called TH1 and TH2 T cells or subsets. But typically the intermediate forms are much more frequent.

No cytokine or surface antigen constitutes an exclusive marker for any CD4 phenotype: for example, IL-10 can be produced by CD4+ T cells of the TH2 characteristics but also by many TH1 cells in human and by many non T cells.136 IFN-y is a "TH1 cytokine", but most of it is made by other T cells (CD8 T cells and CD4 T cells not fitting the TH1 definition) or by NK cells. We prefer to reserve the term TH1 and TH2 "subsets" for circumstances where we know that discreet populations, rather than a continuum, can be shown to exist. Under most circumstances TH1 and TH2 cytokines are not made by CD4 T cells which fulfill the criteria for TH1 and TH2 subsets.

TH2 cytokines are more important in helping B cells. In vitro the activation of resting B cells to proliferate and differentiate requires cytokines, particularly of the TH2 type, e.g., IL-4, IL-5.137-139 In addition, IL-10 enhances in vitro viability of B cells and upregulates MHC class II expression on resting small dense B cells from mouse spleens.136,139

TH1 cytokines can enhance or suppress B cell responses, according to the relative amounts of IL-2 and IFN-y produced.140,141 IL-2 in large amounts enhances differentiation, proliferation, and Ig production. IFN-y in low concentrations enhances certain antibody responses but in high amounts suppresses both proliferation and Ig secretion and can be cytotoxic to activated B cells. TH2 cytokines favor IgE and IgG1 responses (through IL-4),120 whereas TH1 cytokines in mice induce IgG2a.140

Table 1.4. Some cytokinephenotypes of mouse CD4 T-cell clones

Cytokine Phenotype

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