Differences in maintenance of CD8⁺ and CD4⁺ bacteria‐specific effector‐memory T cell populations

Abstract

Our knowledge about the kinetics and dynamics of complex pathogen-specific CD8 + T cell responses and the in vivo development of CD8 + memory T cells has increased substantially over the past years; in comparison, relatively little is known about the CD4 + T cell compartment. We monitored and directly compared the phenotypical changes of pathogen (Listeria monocytogenes)-specific CD8 + and CD4 + T cell responses under conditions leading to effective and long-lasting protective immunity. We found that the general kinetics of bacteriaspecific CD8 + and CD4 + T cells during the effector and post-effector phases are synchronized. However, later during the memory phase, CD8 + and CD4 + T cell populations differ substantially. Whereas CD8 + memory T cell populations with immediate effector function are readily detectable in lymphoid and non-lymphoid tissues and remain remarkably stable in size, antigen-specific CD4 + effector-memory T cells decline continuously in frequency over time. These findings have important implications for the better understanding of the in vivo development of protective immunity towards intracellular pathogens.

Duration of Infection and Antigen Display Have Minimal Influence on the Kinetics of the CD4+ T Cell Response to Listeria monocytogenes Infection

“…After activation, CD4 ϩ and CD8 ϩ T cells clonally expand and differentiate into effector T cells, that generally peak in number in the spleen and other organs between days 7 and 9 after LM infection (16 -18, 26). After this peak, a contraction phase occurs, in which a majority of the Ag-specific CD4 ϩ and CD8 ϩ T cells die (26). Ag-specific CD4 ϩ and CD8 ϩ T cells that survive the contraction phase persist in the host as memory T cells.…”

“…CD4 ϩ T cells contribute to immunity by promoting dendritic cell (DC) activation (22), secreting inflammatory cytokines that activate the antimicrobial activities of macrophages, and providing help for the Ab response (23). In general, activation of both CD4 ϩ and CD8 ϩ T cell responses requires Ag and costimulation (24,25), and both cell populations exhibit similar overall kinetics of expansion and contraction to memory (26). However, comparison of CD4 ϩ and CD8 ϩ T cell responses to infection have revealed differences that may reflect their differing roles in immunity.…”

“…However, comparison of CD4 ϩ and CD8 ϩ T cell responses to infection have revealed differences that may reflect their differing roles in immunity. For instance, the kinetics of CD4 ϩ and CD8 ϩ T cell responses are synchronized, but over the life of the host, stable numbers of Ag-specific memory CD8 ϩ T cells persist, whereas CD4 ϩ T cell memory declines over time (26,27). In addition, CD8 ϩ T cell memory, but not CD4 ϩ T cell memory, is reduced after heterologous infection (28).…”

“…To circumvent this problem, we infected B6 mice with a recently described recombinant LM strain expressing hen OVA (rLM-OVA) as a secreted protein (38). Infection of B6 mice with rLM-OVA stimulates a vigorous expansion and the generation of memory CD4 ϩ T cells specific for LLO 190 -201 as well as a strong H-2K b -restricted CD8 ϩ T cell response to the well-characterized OVA 257-264 epitope (26). This system allowed us to directly compare CD4 ϩ T cells and CD8 ϩ T cell responses in the same host.…”

CD4 memory T cells divide poorly in response to antigen because of their cytokine profile

“…It is now generally accepted that, as a population, memory CD8 T cells are maintained at fairly constant numbers (3) and provide protection more effectively than naïve cells (4). In contrast, the maintenance and functional capabilities of memory CD4 T cells are still controversial (5)(6)(7)(8)(9).…”