There are three important subpopulations of T Lymphocytes (T cells): helper T cells, which interact with B cells to amplify production of antibody; effector T cells, which carry out the direct cell-killing function of T cells and make certain lymphokines (non-antibody products) which are responsible for delayed hypersensitivity; and supressor T cells, which participate in the regulation of both antibody-medicated and cell-mediated immunity.
T cells must be activated before any of these forms of activity are expressed. Usually the activation follows from exposure to antigen, but other less specific factors such a interleukin 2 are also believed to participate in the activation of T cells.
Usually there is a latent period of around a week to 10 days after first exposure to antigen before the T cells develop initial reactivity. Shortly after that the reactivity subsides. Upon a second contact with antigen, T cells show an accelerated memory response with high activity developing within 2-5 days.
The addition of antigen to cultured lymphocytes induces a small proportion of T cells to differentiate into the large rapidly dividing blast cells. T cells can also be transformed by culturing them together with the lymphocytes of individuals of the same species, a so-called mixed lymphocyte culture. Because of extensive polymorphism at HLA loci, the two cell populations are virtually always different antigenically and they stimulate each other to undergo blast transformation. For example, isolated blood lymphocytes from recipient and prospective donor are maintained together for several days in tissue culture. Blast transformation occurs if allogenic cells are present. This process may be referred to as alloactivation. Mixed lymphocyte cultures may be established by treating one set of cells in a manner that prevents blast transformation of that set of cells such as irradiating the cells.
A T lymphocyte will recognize an antigen only if the antigen is properly presented by a presenting cell which in many cases is a macrophage. The antigen must be presented juxtaposed to a compatible Ia molecule, a surface molecule coded for by one of the class I transplantation or histocompatibility genes. In man, there are at least two distinct families of Ia molecules encoded by mixed lymphocyte culture genes, HLA-DR and MT or DS. These genes control the formation of the specialized complementary Ia structures on the surface of a presenting cell and the T cells that provide for proper presentation of antigens. T cells may interact with B cells, or other T cells, if the cell possesses complementary Ia structures and if it recognizes the same antigenic determinant or a different determinant on the same antigenic molecule.
During the process of activation, T cells develop new surface antigens, so-called T cell activation antigens. Most of these T cell activation antigens, however, are not T cell specific. For example, the transferrin receptor, the insulin receptor and the 4F2 antigen appear on proliferating cells of many types. Only one T cell activation antigen, Tac (Interleukin-2 receptor), is found only on activated T cells.
The kinetics of antigen appearance on activated T cells has been studied in order to gain some insight into the function of these molecules. Cotner et al. examined the kinetics of appearance of several T cell antigens and found that each exhibited a characteristic and reproducible time of appearance (9). Based upon this, the antigens could be classified as early, intermediate or late appearing antigens.
The relevancy of various cell surface markers to the functional heterogeneity of alloreactive T cell clones has been examined and the rearrangement of the T B-chain gene of the antigen receptor in wild and mutant variants of clones with altered phenotypes and function compared (7). BALB/C mice have been immunized with helper T cell clones to produce two monoclonal antibodies which detect distinct cell surface molecules associated with T cell helper activity and with the production of T replacing factor (8).
The 4F2 antigen, Tac, the 49.9 antigen and the transferrin receptor appear within 24 hours of mitogen stimulation, before the onset of DNA synthesis, and are classified as early antigens. Early appearing antigens may be associated with cell growth. The HLA-DR antigen and the 19.2 antigen (Ia antigen) do not appear until about 72 hours after activation and are classified as late antigens. Expression of the OKT 10 antigen by activated T cells is intermediate.
The molecule or molecules associated with T cell helper function are unknown. Human helper T cells are defined as lymphocytes which express the T4 surface antigen, a T cell specific glycoprotein molecule expressed by cells which recognize and are restricted by major histocompatibility complex class II antigens. This molecule is also found on killer and suppressor lymphocytes suggesting that the T4 molecule is not involved in helper function. Similarly, the T cell antigen receptor does not seem to be involved in any specific T cell function because the gene which encodes the B-chain of the receptor is rearranged and expressed by helper, suppressor and cytotoxic T cells.