Regulation of in vivo immune responses: few principles and much ignorance.

An attempt is made, based largely on reports of experiments carried out in vitro, to piece together the sequence of events between the interaction of antigens with B or T lymphocytes and the immune responses which result. These include stimulation of B lymphocytes to secrete antibody or to become B memory cells, and stimulation of T helper cells and cytotoxic/suppressor T cells to multiply and become functional effector cells. Thymus-independent (T1) stimulation is described of a subpopulation of B cells by poorly degradable immunogens with multiple epitopes, and the generation of B memory cells, as well as stimulation of B cells requiring cooperation with T cells. Stimulation of T helper (TH) cells by antigens involves first activation by interleukin 1 (IL-1) and then presentation of the antigen at the surface of antigen-presenting cells (usually macrophages, dendritic cells or B cells) in association with class II major histocompatibility complex molecules (MHC II); for extrinsic (foreign) proteins this requires initial capture of the protein, followed by denaturation and/or degradation so as to associate the molecule or fragments with MHC II. Some peptides can become suitably associated without further degradation, whereas T1 antigens may be unable to become associated effectively. T cells so stimulated express receptors for interleukin 2 (IL-2), and secrete various molecules, including factors which stimulate B cells to divide and/or secrete Ig, interferon-gamma and IL-2. In turn, IL-2 causes proliferation of TH and cytotoxic/suppressor T cells. Interferon-gamma stimulates the expression of MHC II by macrophages and some epithelial cells and increases the activity of NK (natural killer) cells. This simplified account embraces many of the experimental observations, but there are sufficient exceptions to make clear that much remains to be discovered even in respect of the interactions of antigen-presenting cells, T cells and B cells in vitro. Application of such general principles to predict the outcome of immunization in vivo would need also to take into account the microenvironments in lymphoid tissues where antigens are retained, and the flow of lymphocytes through them; how long the antigens persist; and how the immune response is modified by responses already elicited, including the idiotype network. Because such information is not usually available, enlightened guess-work may still be the best guide to practice.