Heterogeneity and cell-fate decisions in effector and memory CD8+ T cell differentiation during viral infection

Abstract

Heterogeneity is a hallmark of the adaptive immune system. This is most evident in the enormous diversity of B and T cell antigen receptors. There is also heterogeneity within antiviral T cell populations, and subsets of effector and memory T cells now permeate our thinking about specialization of T cell responses to pathogens. It has been less clear, however, how heterogeneity in developing virus-specific effector and memory T cells is related to cell-fate decisions in the immune response, such as the generation long-lived memory T cells. Here we discuss recent findings that might help redefine how heterogeneity in antiviral T cell populations gives rise to T cell subsets with short- and long-lived cell fates.

Figure 1. A Homogenous and Heterogeneous View on Antiviral Memory T Cell Development

(A) T cells clonally expand and homogeneously differentiate into effector T cells, of which most die, but some persist to become long-lived memory T cells. Upon reinfection, memory T cells re-expand and control infection faster than 1° infection. (B) Two populations of effector T cells form with different memory T cell potential: short-lived effector T cells (SLECs; yellow line) that do not gain memory T cell potential, and memory precursor effector cells (MPECs; blue line) that do. Upon reinfection, it is primarily the descendents of MPECs that participate in secondary responses because of their enhanced proliferative capacity.

Figure 2. Models of Effector and Memory Cell-Fate Decisions during Acute Viral Infection

Model 1—uniform potential. All activated effector cells develop equal potential to become MPECs (aqua cells), but extrinsic factors limit the number of memory T cells generated. MPECs give rise to transitional T_EM cells (gray) that convert into self-renewing T_CM cells (dark blue). Model 2—decreasing potential. Shorter durations of antigenic stimulation favor MPECs that give rise to T_CM cells. Longer stimulation promotes terminal differentiation of SLECs (yellow) and end-stage T_EM cells (green) that decline over time. Model 3—fixed lineage. Upon activation, naive T cells develop into either SLECs or fully mature memory T cells. In this model, cells might bypass an effector stage and develop directly into self-renewing T_CM. Model 4—fate commitment with progressive differentiation. According to the strength of signal, either an MPEC or SLEC fate will be adopted early after activation. The MPECs acquire effector functions, but remain multipotent (e.g., can still become memory T cells or SLECs). Most SLECs die, but some persist with a limited lifespan as an end-stage T_EM cell. MPECs survive, and give rise to transitional T_EM cells that progressively mature into long-lived T_CM cells.

Figure 3. Differential Effects of Acute, Latent or Chronic Viral Infections on Memory T Cell Differentiation

Viral infections fall into three categories based on the duration and pattern of viral infection—(1) acute, (2) latent with reactivation, and (3) chronic or persistent. Primary acute infection generates SLECs (yellow) and MPECs (aqua). For a description of the cell types, see Figure 2. The majority of SLECs die, but some persist for finite intervals (T_EM cells; green). In contrast, MPECs survive and progressively mature from transitional T_EM cells (light blue) into protective T_CM cells (dark blue). During latent or reactivating viral infections, a mixed population with a variety of effector and memory differentiate states is formed. Typically, there will be more SLECs and T_EM cells than after acute infection. The abundance of secondary MPECs, resting T_CM cells, or transitional T_EM cells will likely depend on the frequency and degree of viral reactivation. During persistent or chronic viral infections, with high viremia, T cells can undergo altered differentiation and become exhausted (red). According to the type of infection, the snap-shot of effector and memory T cells present (outlined in red box) is likely to be different. See Table 1 for detailed descriptions of common attributes.