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Quantitative Regulation of B Cell Division Destiny by Signal Strength

Marian L. Turner^*,, Edwin D. Hawkins^*, and Philip D. Hodgkin^1,*

^* Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; and Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia

Differentiation to Ab secreting and isotype-switched effector cells is tightly linked to cell division and therefore the degree of proliferation strongly influences the nature of the immune response. The maximum number of divisions reached, termed the population division destiny, is stochastically distributed in the population and is an important parameter in the quantitative outcome of lymphocyte responses. In this study, we further assessed the variables that regulate B cell division destiny in vitro in response to T cell- and TLR-dependent stimuli. Both the concentration and duration of stimulation were able to regulate the average maximum number of divisions undergone for each stimulus. Notably, a maximum division destiny was reached during provision of repeated saturating stimulation, revealing that an intrinsic limit to proliferation exists even under these conditions. This limit was linked directly to division number rather than time of exposure to stimulation and operated independently of the survival regulation of the cells. These results demonstrate that a B cell population’s division destiny is regulable by the stimulatory conditions up to an inherent maximum value. Division destiny is a crucial parameter in regulating the extent of B cell responses and thereby also the nature of the immune response mounted.

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¹ Address correspondence and reprint requests to Dr. Philip D. Hodgkin, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia. E-mail address: Hodgkin{at}wehi.edu.au

² Abbreviations used in this paper: HEL, hen egg lysozyme; ASC, Ab-secreting cell.