Divide and conquer: the importance of cell division in regulating B-cell responses

Abstract

Proliferation is an essential characteristic of clonal selection and is required for the expansion of antigen reactive clones leading to the development of antibody of different isotypes and memory cells. New data for mouse and human B cells point to an important role for division in regulating isotype class and in optimizing development of protective immunity by the regulated entry of cells to the plasma cell lineage.

Figure 1

The division hypothesis and stochastic division-linked regulation of isotype switching, antibody secretion and memory. (a) Resting IgM⁺ B cells are activated to proliferate following exposure to antigen (Ag). The combination of signals received, as well as intrinsic internal ‘programming’, dictates the progressive change in the probability of switching to a new isotype per division. Switched cells are shown as the blue cells at the top of the diagram. Both switched and unswitched cells undergo differentiation to immunoglobulin (Ig)-secreting cells (ISCs) at a similar rate, giving rise to Ig. When Ag stimulation ceases, the pool of activated cells undergoes contraction, as a result of apoptosis, leaving a core of switched and unswitched memory cells as well as long-lived ISCs (plasma cells). Upon restimulation, memory cells differentiate to ISCs more rapidly per division than naïve cells. (b) The top panel shows how the rate of switching can be represented as a probability map showing the proportion of undifferentiated cells that will change between each division cycle. The relation between arrow strength in (a) and probability is given for illustration. The middle panel shows how alternative differentiation events can have a different relation to division number. IgG1 switching in response to interleukin (IL)-4 proceeds earlier than IgE switching. The bottom panel shows how the relation to division can be modified by changing the cytokine concentration. (c) The bottom panel shows a putative set of overlapping differentiation maps associated with the combination of stimuli received during B-cell activation. The two top panels show how cells dividing according to this scheme will automatically generate considerable heterogeneity. The colour of the cells corresponds to the colour of the symbols on the map. The top panels also illustrate how two different rates of Ag persistence can drive the cells to different patterns and mixtures of cell types. After a period of contraction, the isotype mix of the memory (Mem) cells and long-lived ISCs will be different.

Figure 2

A stochastic division-linked model of plasma cell generation. Memory B cells stimulated with T cells begin dividing and continue to divide as long as T-cell-derived signals, including CD40L, are maintained. Memory B-cell blast expansion therefore requires frequent serial contact with T cells. Throughout the life of the memory blast, a stochastic mechanism is operating that directs the transition to an immunoglobulin-secreting cell (ISC) (either CD38^– or CD38⁺) according to a regulable probability. In early divisions, the probability is low; however, it increases with consecutive divisions, resulting in a greatly enhanced rate of plasmablast formation later in the response (shown by thickening arrows). CD38⁺ ISCs (i.e. plasmablasts) are no longer dependent on CD40L, and therefore do not require serial contact with T cells. Consequently, these cells can proliferate in the presence of T-cell-derived cytokines only (e.g. IL-10). Presumably these plasmablasts have altered migration properties and home to sites where further plasma cell (PC) maturation occurs. Plasmablasts and their early expansion contribute to the initial, rapid antibody response. The long-lived, Ag-independent non-dividing PCs are responsible for persistent antibody well after the Ag is removed.

Figure 3

B-cell activating factor belonging to the tumour necrosis factor (TNF) family (BAFF) supports the survival of CD38⁺ plasmablasts: a schematic outline of how interactions between T cells, memory B cells and dendritic cells (DCs) contribute to facilitate the generation of immunoglobulin-secreting cells (ISCs). The same T-cell-derived signals that drive B-cell proliferation and differentiation (i.e. CD40L, IL-2 and IL-10) stimulate DCs to produce BAFF (and also IL-10). Thus, DC-derived BAFF may act as a survival factor for de novo generated ISCs, which lose dependence on CD40L, while undifferentiated memory B-blasts remain dependent on T-cell help for their survival. BCMA, B cell maturation antigen.

Figure 4

Optimizing the rate of immunoglobulin-secreting cells (ISC) formation while preserving the memory compartment. The stochastic, division-linked model of ISC formation is presented under different values for the maximum level and contrasted with a linear model of differentiation. (a) The frequency of ISCs formed by the end of each division number is given as a normal distribution with a mean division number of 6 and a standard deviation of 1·5 divisions. The maximum frequency at division 6 is varied and set to either (b) 10%, (c) 20%, (d) 40% or (e) 60%. The numbers of memory blasts (○) and ISCs (•) are calculated before each consecutive division and plotted as shown (b–e) from a starting number of 10⁴ cells. The ISCs are not set to divide in this calculation to better illustrate their time of appearance. Division time in this model is synchronized and set arbitrarily at 40 hr for the first division, and at 15 hr for each subsequent division. (f) The frequencies of ISC formation for the ‘linear’ model of differentiation, where the rate per division is held constant. The results of the linear model with the frequency of memory blasts forming ISCs per division set at (g) 10%, (h) 20%, (i) 40% or (j) 60% are shown.