The importance of division progression in regulating lymphocyte differentiation
T and B lymphocytes respond to antigen in numerous ways. On the one hand they can be tolerized and fail to mount a response, or, alternatively they can undertake a vigorous proliferative response. If the latter the cells also undergo differentiation to alternative immune ‘classes’. For B cells class choices are reflected in the selection of antibody isotypes such as IgG or IgE. For T cells a range of cytokines can be expressed that influence their ability to eliminate different classes of infectious agent. We discovered that the expression of different isotypes by B cells, and cytokines by T cells, alters with division progression. Thus, for B cells stimulated in the presence of the cytokine IL-4 the frequency of cells that express IgG1 increases through divisions 4-7 and is followed by expression of IgE in later divisions. The development of antibody secreting cells also progressively increases as cells divide. As isotype switching and development into secreting cells act independently within cells proliferation results in the automatic generation of switched and unswitched antibody secreting cells. Thus, as a default, B cells driven to proliferate automatically differentiate and change the class of response.
We have also found that exposure to regulatory cytokines can alter the relationship with division, effectively changing the probability of differentiating associated with a division. As many differentiation processes are associated with division, ‘maps’ of change for T and B lymphocytes can be developed.
We are exploring division-linked behaviour to gain clues as to the evolution and regulation of different immune response classes and how they are invoked by different types of pathogen.