Early programming and late‐acting checkpoints governing the development of CD4 T‐cell memory

Abstract

CD4 T cells contribute to protection against pathogens through numerous mechanisms. Incorporating the goal of memory CD4 T-cell generation into vaccine strategies therefore offers a powerful approach to improve their efficacy, especially in situations where humoral responses alone cannot confer long-term immunity. These threats include viruses such as influenza that mutate coat proteins to avoid neutralizing antibodies, but that are targeted by T cells that recognize more conserved protein epitopes shared by different strains. A major barrier in the design of such vaccines is that the mechanisms controlling the efficiency with which memory cells form remain incompletely understood. Here, we discuss recent insights into fate decisions controlling memory generation. We focus on the importance of three general cues: interleukin-2, antigen and co-stimulatory interactions. It is increasingly clear that these signals have a powerful influence on the capacity of CD4 T cells to form memory during two distinct phases of the immune response. First, through 'programming' that occurs during initial priming, and second, through 'checkpoints' that operate later during the effector stage. These findings indicate that novel vaccine strategies must seek to optimize cognate interactions, during which interleukin-2-, antigen- and co-stimulation-dependent signals are tightly linked, well beyond initial antigen encounter to induce robust memory CD4 T cells.

Memory CD4+ T Cells in Immunity and Autoimmune Diseases

“…IL-2, via regulation of Bcl-6 expression, also plays fundamental roles in memory CD4 T cell development [63][64][65]. Current dogma suggests that naïve CD4 + T cells require high levels of IL-2 to differentiate into memory precursor cells; however, these precursor cells are then dependent on low levels of IL-2 to develop into long-lived memory cells.…”

“…Although CD4 + TRM were reported to express low levels of T-bet [62], suggesting that this pathway is dispensable for CD4 TRM maintenance, future work should investigate the role of T-bet-promoting cytokines for regulating CD4 + TRM development, since this has not yet been fully resolved. IL-2, via regulation of Bcl-6 expression, also plays fundamental roles in memory CD4 T cell development [63][64][65]. Current dogma suggests that naïve CD4 + T cells require high levels of IL-2 to differentiate into memory precursor cells; however, these precursor cells are then dependent on low levels of IL-2 to develop into long-lived memory cells.…”

Origins of CD4+ circulating and tissue‐resident memory T‐cells

“…In fact, IL‐15 was shown to be essential for these IL‐2‐independent cells, acting as an ‘alarm’ at local sites of infection to promote both CD8 + T‐cell responses and induce long‐lived CD4 + T RM. Using fluorescently labelled antibody injection, Hondowicz et al . showed that LCMV‐specific CD4 + T‐cells migrated to the lungs as a Tbet hi T H 1 subset with CD69 expression similar to influenza experiments.…”

“…A recent comprehensive review of studies aimed at resolving the signals required for CD4 + memory T‐cell formation discussed the instructive signals both during the ‘early priming’ phase of initial antigen recognition and activation as well as at ‘late‐acting checkpoints’ prior to contraction that play a role in the effector‐to‐memory transition. Much like the signals important for CD8 + memory T‐cell generation, strengths of TCR and co‐stimulatory signalling also have profound effects on memory T H development . Recent results from Snook et al .…”

“…Much like the signals important for CD8 + memory T-cell generation, strengths of TCR and co-stimulatory signalling also have profound effects on memory T H development. 42,43 Recent results from Snook et al 44 demonstrated that TCR signalling has a direct impact on T H memory formation. Utilizing a panel of TCRs specific for the same viral antigen, the authors showed substantial variability in TCR signal strength, expression of IL-2-receptor alpha (CD25) and activation of downstream TFs across the CD4 + memory T-cell population.…”