The quantal theory of how the immune system discriminates between "self and non-self"

Abstract

In the past 50 years, immunologists have accumulated an amazing amount of information as to how the immune system functions. However, one of the most fundamental aspects of immunity, how the immune system discriminates between self vs. non-self, still remains an enigma. Any attempt to explain this most intriguing and fundamental characteristic must account for this decision at the level of the whole immune system, but as well, at the level of the individual cells making up the immune system. Moreover, it must provide for a molecular explanation as to how and why the cells behave as they do. The "Quantal Theory", proposed herein, is based upon the "Clonal Selection Theory", first proposed by Sir McFarland Burnet in 1955, in which he explained the remarkable specificity as well as diversity of recognition of everything foreign in the environment. The "Quantal Theory" is built upon Burnet's premise that after antigen selection of cell clones, a proliferative expansion of the selected cells ensues. Furthermore, it is derived from experiments which indicate that the proliferation of antigen-selected cell clones is determined by a quantal, "all-or-none", decision promulgated by a critical number of cellular receptors triggered by the T Cell Growth Factor (TCGF), interleukin 2 (IL2). An extraordinary number of experiments reported especially in the past 20 years, and detailed herein, indicate that the T cell Antigen Receptor (TCR) behaves similarly, and also that there are several critical numbers of triggered TCRs that determine different fates of the T cells. Moreover, the fates of the cells appear ultimately to be determined by the TCR triggering of the IL2 and IL2 receptor (IL2R) genes, which are also expressed in a very quantal fashion. The "Quantal Theory" states that the fundamental decisions of the T cell immune system are dependent upon the cells receiving a critical number of triggered TCRs and IL2Rs and that the cells respond in an all-or-none fashion. The "Quantal Theory" accounts fully for the development of T cells in the thymus, and such fundamental cellular fates as both "positive" and "negative" selection, as well as the decision to differentiate into a "Regulatory T cell" (T-Reg). In the periphery, the "Quantal Theory" accounts for the decision to proliferate or not in response to the presence of an antigen, either non-self or self, or to differentiate into a T-Reg. Since the immune system discriminates between self and non-self antigens by the accumulated number of triggered TCRs and IL2Rs, therapeutic manipulation of the determinants of these quantal decisions should permit new approaches to either enhance or dampen antigen-specific immune responses.

Figure 1

The IL2 binding and biological response curves are coincident. Radiolabeled IL2 and purified homogeneous IL2 were used in parallel experiments with the same IL2R+ T cell population to determine the relationship between IL2 binding and IL2-promoted T cell proliferation as monitored by ³H-TdR incorporation. From reference 25.

Figure 2

The IL2 biological dose-response relationship is determined at the single cell level by a marked heterogeneity of responsiveness. Asynchronously proliferating IL2R+ cells were exposed to varying concentrations of IL2 for 18 hours. Subsequently, cell aliquots were either pulsed for 4 hours with ³H-TdR, or stained with propidium iodide prior to single cell analysis by flow cytometry. The cell population incorporates ³H-TdR in an IL2 concentration dependent manner, and the amount of ³H-TdR incorporation at each IL2 concentration is determined by the absolute number of cells that have entered S-phase, as indicated by the single cell analysis by propidium iodide staining. From reference 26.

Figure 3

The effect of IL2R density on the rate of T cell cycle progression. Two G_0/1 synchronized T cell populations that differed 3-fold in mean IL2R density were exposed to an IL2R saturating concentration (250 pM) for 48 hours and ³H-TdR incorporation was monitored as indicated at 1 hour intervals. The cells with the higher IL2R density (solid circles) entered S-phase before the cell population with the lower IL2R density (solid triangles). From reference 26.

Figure 4

IL2R density determined at the single cell level by flow cytometry. IL2R+ T cells were labeled with anti-Tac (CD25) monoclonal antibody and analyzed by single cell flow cytometry. The IL2R density varies among cells within he population over 3 orders of magnitude. From reference 26.

Figure 5

The effect of varying the IL2 exposure period on the proliferative response of G_0/1 synchronized IL2R+ T cells. Aliquots of synchronized cells were exposed to IL2 for varying intervals (3, 6, 11, 26 hours) then washed and placed into culture without IL2 and pulsed with ³H-TdR. Symbols: IL2 exposure, 3 hr (solid circles), 6 hr (open circles), 11 hr (solid triangles), and 26 hr (open triangles). Inset, shows the ³H-TdR incorporation of each cell population in response to an IL2R saturating IL2 concentration (250 pM) monitored for 1 hr at the times indicated. From reference 26.

Figure 6

The number of triggered TCRs and IL2Rs determine quantal T cell fates in both the thymus and the periphery. On each plot, the number of triggered TCRs and IL2Rs increase from bottom to top. The different quantal cell fates are dictated by a definite number of triggered Rs as depicted.