Transplanting B Cells from Old Mice to Young Mice to Investigate Details of B Cell Aging
The varieties of B cell in the immune system participate in the immune response to pathogens by creating antibodies to match specific antigens, and spreading the information represented by that antibody to portions of the adaptive immune system capable of attacking threats. This is a very crude, high level summary of an enormously complex system. The fine details of how subsets of the B cell population generate suitable antibodies, and then communicate with one another and the rest of the immune system, are complicated indeed, involving many different subsets of cell, different paths of activation, and different mechanisms.
Aspects of B cell function are known to decline with age, contributing to the broader loss of efficacy in the immune response, the onset of immunosenescence. Is this a problem with the B cells themselves becoming changed or damaged, or is it a problem of the broader system within which B cells function? This sort of question is always hard to answer in the study of aging. Biology is very complicated, and everything interacts with everything else. Isolating the specifics of any one mechanism amidst all of that is very challenging. There are always avenues by which to make some progress, however. In today's open access paper, researchers analyze the behavior of B cells transplanted from old mice into young mice, using this as a strategy to obtain some insight into which aspects of B cell function decline due to intrinsic defects in the aged cells, and which are due to age-related deficiencies in other parts of the immune system.
Interestingly, other work shows that B cells can be readily cleared from the body in old animals, and regenerate rapidly following this intervention. Immune function is improved as a result. Thus while the work here shows that old B cells remain surprisingly functional if only given a young immune system to work with, there is in fact a degradation of function that is distinct from any problem in the hematopoietic cell populations responsible for creating B cells. Some populations of problem B cells have been identified, described as age-associated B cells in the literature, and it seems we'd all be better off for their removal from the aging body.
Vaccines typically protect against (re)infections by generating pathogen-neutralising antibodies. However, as we age, antibody-secreting cell formation and vaccine-induced antibody titres are reduced. Antibody-secreting plasma cells differentiate from B cells either early post-vaccination through the extrafollicular response or from the germinal centre (GC) reaction, which generates long-lived antibody-secreting cells. As the formation of both the extrafollicular antibody response and the GC requires the interaction of multiple cell types, the impaired antibody response in ageing could be caused by B cell intrinsic or extrinsic factors, or a combination of the two.
Here, we show that B cells from older people do not have intrinsic defects in their proliferation and differentiation into antibody-secreting cells in vitro compared to those from the younger donors. However, adoptive transfer of B cells from aged mice to young recipient mice showed that differentiation into extrafollicular plasma cells was favoured at the expense of B cells entering the GC during the early stages of GC formation. In contrast, by the peak of the GC response, GC B cells derived from the donor cells of aged mice had expanded to the same extent as those from the younger donors. This indicates that age-related intrinsic B cell changes delay the GC response but are not responsible for the impaired antibody-secreting response or smaller peak GC response in ageing.
Collectively, this study shows that B cells from aged individuals are not intrinsically defective in responding to stimulation and becoming antibody-secreting cells, implicating B cell-extrinsic factors as the primary cause of age-associated impairment in the humoral immunity.