Understanding the Heterogeneous Population of Age-Associated B Cells and Their Contributions to Autoimmunity and Immune Response to Pathogens

Abstract

In humans and mice, susceptibility to infections and autoimmunity increases with age due to age-associated changes in innate and adaptive immune responses. Aged innate cells are also less active, leading to decreased naive T- and B-cell responses. Aging innate cells contribute to an overall heightened inflammatory environment. Naive T and B cells undergo cell-intrinsic age-related changes that result in reduced effector and memory responses. However, previously established B- and T-cell memory responses persist with age. One dramatic change is the appearance of a newly recognized population of age-associated B cells (ABCs) that has a unique cluster of differentiation (CD)21-CD23- phenotype. Here, we discuss the discovery and origins of the naive phenotype immunoglobulin (Ig)D+ versus activated CD11c+T-bet+ ABCs, with a focus on protective and pathogenic properties. In humans and mice, antigen-experienced CD11c+T-bet+ ABCs increase with autoimmunity and appear in response to bacterial and viral infections. However, our analyses indicate that CD21-CD23- ABCs include a resting, naive, progenitor ABC population that expresses IgD. Similar to generation of CD11c+T-bet+ ABCs, naive ABC response to pathogens depends on toll-like receptor stimulation, making this a key feature of ABC activation. Here, we put forward a potential developmental map of distinct subsets from putative naive ABCs. We suggest that defining signals that can harness the naive ABC response may contribute to protection against pathogens in the elderly. CD11c+T-bet+ ABCs may be useful targets for therapeutic strategies to counter autoimmunity.

Figure 1:. Age-Associated Changes in T cell and B cells.

With age, the number of naïve B cells and T cells decreases leading to a smaller TCR and BCR populations and repertoires. Upon pathogen exposure, naïve CD4 T cells secrete less IL-2 leading to lower effector T cell responses including T follicular helper cells (Tfh). Lower Tfh responses decrease GCB responses, which leads to fewer memory B cells and antibody-secreting cells towards newly encountered pathogens. However, memory B cells from previous immune responses accumulate with age leading to a larger memory B cells pool in the aged.

Figure 2:. B cell responses shift to PR-dependent mechanisms with age

With age, humans and mice experience higher antigen exposure and an increased proinflammatory environment. Furthermore, the number of FOB, MZB and B1b/a cells decrease as ABC accumulate with age. This can be replicated in chronically infected and autoimmune-prone young mice, which accumulate CD11c⁺Tbet⁺ ABC. T-cell responses also decrease leading to a higher dependence on PR signals. Unlike, T-cell dependent FOB, ABC can be T-independent, and their activation depends on higher Ag exposure and PR signals. Thus, they can mount a primary response to new pathogens, which may provide protection.

Figure 3:. Proposed relationship between naive and primed ABC

Our studies show that with high Ag and PR exposure, naïve ABC can become active ABC which express Fas and differentiate into Ab-producing cells. We termed this subset as induced age associated B cells (iABC). Although autoimmune ABC can accumulate in young mice, we propose that this primed subset may also arise from naïve ABC with multiple Ag exposures and heightened inflammatory environment. Like iABC effectors, this autoimmune ABC differentiates into Ab-producing cells which produces autoantibodies.

Figure 4:. Proposed Vaccine Strategies to Enhance Response in the Elderly

Studies show that memory T and B cell response increase with age and may provide protection against reoccurring infection. One way of enhancing the aged immune system is by increasing exposure to Ag by vaccination in young or middle-aged populations in order to increase the size of the memory repertoire later. Another way of enhancing aged immune responses is by providing higher doses of Ag and TLR-signaling to antigen-presenting cells (APC). These should lead to optimal naïve aged T and B cells responses and help establish new memory T and B cells responses to new pathogens.