Speculations on the evolution of humoral adaptive immunity

Abstract

The protection of a multicellular organism from infection, at both cell and humoral levels, has been a tremendous driver of gene selection and cellular response strategies. Here we focus on a critical event in the development of humoral immunity: The transition from principally innate responses to a system of adaptive cell selection, with all the attendant mechanical problems that must be solved in order for it to work effectively. Here we review recent advances, but our major goal is to highlight that the development of adaptive immunity resulted from the adoption, reuse and repurposing of an ancient, autonomous cellular program that combines and exploits three titratable cellular fate timers. We illustrate how this common cell machinery recurs and appears throughout biology, and has been essential for the evolution of complex organisms, at many levels of scale.

Keywords: B cells; cell fate; cell signaling; comparative immunology; evolutionary immunology; humoral immunity; proliferation.

Figure 1

Three ancient cell fate timers combine for ubiquitous tissue patterning outcomes. (a) The basic program of the 3‐TM. Engaging the receptor (or receptors) motivates separate modular cellular changes that initiate (1) division; (2) the duration of division and (3) the time to die. Note that the times for 2 and 3 can be inherited and passed to progeny. (b) The net effect of each timer applied in sequence, leading to the automatic increase and timed loss of the stimulated cell and subsequent clonal family over time. (c, d) These diagrams show how similar autonomic mechanical features underlie the B‐cell response, insect wing development and the growth of the intestinal crypt. Additional modular cell fate programs that interleave with 3‐TM are represented below the dashed line. These may include the integration of further signals as in c, or may function as additional independent modules that regulate differentiation fates. These fates may function as timers, as with the components of the 3‐TM, or could use cell division as a “counting” mechanism, with a threshold number of divisions triggering a cell fate decision. 3‐TM, three‐timer model; CDK, cyclin‐dependent kinase; cell #, cell number; DIV, division; t, time.

Figure 2

Key steps in humoral immune cell evolution. (a) Simple intrinsic secretion of natural antibodies or agglutinins into fluid spaces for B‐1 cells in vertebrates, but also observed for agglutinins, defensins and lectins in other, more primitive species. (b) Germline‐coded receptors of varying degrees of diversity trigger a limited expansion and therefore increased production of secreted material but with minimal further diversification of effector activity. This is seen for the CpG response in vertebrates, but also for hemocyte activation and contraction in insects, including stochastic splicing to diversify and select Dscam protein variants by Drosophila. (c) Diversification of receptor and coupling to the same 3‐TM limited, intrinsic response program. (d) Coupling of further effector fate changes to 3‐TM responses by time and/or division to diversify and engage selected specificities with alternative immune strategies. This latter set of programs can be subject to a high degree of feedback and further cell signaling to fine‐tune and optimize the effective outcomes. Some activated cells also enter and seed the germinal center response and undergo repeated cycles analogous to 3‐TM expansion and loss that include timed Myc‐dependent proliferation initiated by B‐cell receptor and T‐cell signals, with cells shuttling between light zone (LZ) and dark zone (DZ) regions and this results in the selection of high‐affinity cells. 3‐TM, three‐timer model; cell #, cell number; Diff, differentiation; t, time.