Mechanisms that determine plasma cell lifespan and the duration of humoral immunity

Abstract

Humoral immunity following vaccination or infection is mainly derived from two types of cells: memory B cells and plasma cells. Memory B cells do not actively secrete antibody but instead maintain their immunoglobulin in the membrane-bound form that serves as the antigen-specific B-cell receptor. In contrast, plasma cells are terminally differentiated cells that no longer express surface-bound immunoglobulin but continuously secrete antibody without requiring further antigenic stimulation. Pre-existing serum or mucosal antibody elicited by plasma cells (or other intermediate antibody-secreting cells) represents the first line of defense against reinfection and is critical for protection against many microbial diseases. However, the mechanisms involved with maintaining long-term antibody production are not fully understood. Here, we examine several models of long-term humoral immunity and present a new model, described as the 'Imprinted Lifespan' model of plasma cell longevity. The foundation of this model is that plasma cells are imprinted with a predetermined lifespan based on the magnitude of B-cell signaling that occurs during the induction of an antigen-specific humoral immune response. This represents a testable hypothesis and may explain why some antigen-specific antibody responses fade over time whereas others are maintained essentially for life.

Figure 1

Models of sustained humoral immunity. Several memory B‐cell (MBC)‐dependent and ‐independent models have been developed to explain how long‐term antibody responses are maintained. In this figure, we illustrate how antigen‐specific antibody responses might be maintained under the different proposed models. Chronic infection or cross‐reactivity to either self or environmental antigens is expected to stimulate memory B cells to proliferate and differentiate into antibody‐secreting daughter cells and result in increasing antibody responses over time due to continuous stimulation and accumulation of memory B cells and plasma cells. Repeated infection or booster vaccination will likely lead to periodic increases in antigen‐specific memory B‐cell activation and subsequent increases in antibody responses that would decline during the intervening periods between outbreaks or vaccinations. Persisting antigen in the form of antibody:antigen immune complexes on the surface of follicular dendritic cells (FDCs) will stimulate memory B cells in an antigen‐specific manner, resulting in antibody responses that will decline at the rate of antigen decay or consumption by the memory B‐cell pool. Non‐antigen‐specific polyclonal memory B‐cell stimulation by Toll‐like receptor (TLR) engagement or bystander T‐cell activation will trigger antibody responses to spike during heterologous infections or vaccinations and increase antibody responses to all pre‐existing antibody specificities. Alternatively, long‐term antibody responses may be maintained by long‐lived plasma cells (PCs), and two models are proposed. One model is based on plasma cell competition for space in the bone marrow in which pre‐existing plasma cells are dislodged by incoming plasmablasts, and antibody responses decline as a function of plasma cell displacement. Since there is finite space in the bone marrow, this model would suggest that antibody responses will decline more rapidly during advanced age as a function of increased competition in the bone marrow compartment. Another model of long‐lived plasma cells is based on the theory that plasma cells are imprinted with a specified lifespan, which is determined during the induction phase of the antigen‐specific antibody response.

Figure 2

Longitudinal analysis of antigen‐specific antibody responses in two representative subjects. Antigen‐specific serum antibody responses were followed in two subjects from the Oregon National Primate Research Center (ONPRC) cohort (1) and show the durability of humoral immunity during middle age (Subject 1) and more advanced age (Subject 2). Both subjects were vaccinated against tetanus and diphtheria, and Subject 1 also received smallpox vaccination (i.e. vaccinia virus infection). Antibody responses were determined by ELISA as previously described (1). VZV, varicella‐zoster virus; EBV, Epstein–Barr virus.

Figure 3

The Imprinted Lifespan Model of long‐term antibody maintenance. As shown in Table 1 , antibody responses to specific virus and vaccine antigens have significantly different lifespans. Since plasma cells secrete antibody and consequently lose expression of the membrane‐bound forms of immunoglobulin, it is unlikely that they can detect or respond to specific antigen in their environment. It is thus suggested that the antigen‐specific imprinting of the antibody response must occur during the interface between B cells and antigen during the induction of the humoral immune response. In this model, the combined signals through the B‐cell receptor and signals obtained through CD4⁺ T‐cell help will dictate the lifespan of antibody‐secreting plasma cells. For instance, if B cells are exposed to soluble, non‐repetitive self protein or an unconjugated free chemical hapten, then there is no cross‐linking of the B‐cell receptor (BCR) and no T‐cell help, resulting in weak and short‐lived antibody responses. If the antigen is highly repetitive, then the BCR will be cross‐linked and increase signal strength to the responding B cell. However, without concomitant T‐cell help, the T‐cell‐independent antibody response remains short‐lived – in the order of a few weeks or months. In contrast, if the antigen contains foreign protein, then the responding B‐cell will receive critical CD4⁺ T‐cell help and induce an antibody response that could last for decades (e.g. tetanus toxoid). If the foreign protein antigen is also highly repetitive (e.g. a protein on the surface of a virus particle), then the combination of increased signaling through the BCR together with CD4⁺ T‐cell help will induce plasma cell progeny with an extended lifespan and potentially provide life‐long immunity against reinfection. Since many microbes have highly repetitive structures (identified through Toll‐like receptor as well as other pattern recognition receptors), the potential risk to the mammalian host is determined by the repetitive nature of the antigen and the availability of T‐cell help.

Figure 4

Kinetics of a prototypical serum antibody response. The kinetics of an antigen‐specific antibody response does not typically follow a single rate of decay but instead will often follow a pattern involving at least three phases of antibody half‐life kinetics. Shortly after the peak in antibody production following acute infection or vaccination, antibody responses will decline rapidly, often at the rate of free IgG protein catabolism and removal from the serum [T _1/2 = 17.5–26 days (74, 75, 76)]. For the next 1–3 years, antibody responses will be more long‐lived but will still decline more rapidly than antibody responses analyzed at >3 years after the antigenic insult when antibody production has reached steady‐state levels (1, 80). During the first 1–3 years after vaccination or infection, the antibody response may be maintained by a combination of memory B‐cell‐dependent mechanisms (e.g. persisting antigen on the surface of FDCs) and memory B‐cell‐independent mechanisms (i.e. long‐lived plasma cells), and in this case, the final, steady state antibody response would only become apparent once the antigen depot has been exhausted and is no longer contributing to the plasma cell pool. An alternative model that is not mutually exclusive to the persisting antigen model is that antibody responses elicited during the first few years after vaccination or infection may be produced by a mixed population of long‐lived and short‐lived plasma cells. Plasma cells with the shortest lifespan will decline over time, which will eventually select for the subset of plasma cells with the longest inherent lifespan. Bearing this in mind, the longevity of a given antigen‐specific antibody response might be considered short‐lived, moderately long‐lived, or very long‐lived, depending on the time frame in which the analysis is performed.