The quantal theory of immunity

I recently read two papers of Kendall Smith on his ‘quantal theory of immunity’ (Cell Research 16, 11 and Medical Immunology 3:3). To start with, it should be noted that the word ‘quantal’ here has nothing to do with quantum theory although Schrödinger’s cat does make a brief cameo appearance in the first paper. The term is used to denote all-or-nothing reactions. In other words as the input to a system is increased continuously there is a threshold where the output changes from a low almost constant level to another much higher almost constant level. The input could be the concentration of a substance surrounding a cell while the output could be the amount of a certain protein produced by the cell.

Smith starts by discussing the ‘clonal selection theory’ of MacFarlane Burnet. In this context it is natural to pose the broad question of the possibility of discovering general theories or laws in biology. These concepts are familiar to us from physics and the question is to what extent they can be adapted to biology. I do not pretend to have a general answer to this. A theory or law in this sense is an idea in science which can be used to explain not just a few phenomena but which gives a pattern which can contribute to explanations in a wide field. An obvious example which comes to mind in biology is natural selection. Burnet’s theory seems to provide an example of this kind in immunology. It says that the ability of the immune system to recognize antigens is localized in certain white blood cells (later identified as the lymphocytes), each of which is specific for one antigen. The number of antigens which can be recognized is enormous and correspondingly there are only very few cells recognizing a given antigen. The large numbers of cells needed to combat a given pathogen are reached by ‘clonal expansion’ – one cell undergoes a population expansion by cell division. The next question is how the immune system manages to cause this proliferation in cases where it is beneficial to the individual and to avoid it in cases where it would be harmful. The quantal theory of immunity is a proposed theory to provide an explanation for this.

Smith’s discussion concentrates on T cells, saying that the case of B cells is similar. The proliferation of T cells is associated to their production of the cytokine IL-2. Thus it is important to understand the causes and effects of the latter. Another important theme which needs to be discussed at this point is the the relation between the behaviour of individual cells and that of cell populations. In an experiment we might measure a property of a population, for instance the total production of IL-2, but it is clear that what is being measured in that case is just an average of what is happening in individual cells. Experiments which focus on the properties of individual cells have revealed that there is a high intrinsic variability in cell populations (and in populations of the organisms whose cells are being studied). It has been suggested that this can provide an evolutionary advantage in some cases.

Let us return to IL-2 of which, as I understand, Smith is more or less the father. The reaction to IL-2 in an individual T cell is quantal. The same is true for the production of IL-2 in response to stimulation of the T cell receptor (together with the co-receptor CD28). The global picture presented in Smith’s papers (seen at low resolution) is the following. The fate of T cells (activation, proliferation, anergy, apoptosis) is determined by the number of T cell receptors stimulated. On the axis representing this number there are several bands representing the different outcomes. Variants of this scheme are presented for T cells in the thymus and in the periphery. Underlying this mechanism there is another similar one where the controlling quantity is the number of occupied IL-2 receptors.

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