The multifaceted role of CD4(+) T cells in CD8(+) T cell memory

Abstract

Following infection, T cells differentiate into a heterogeneous population of effector T cells that can mediate pathogen clearance. A subset of these effector T cells possesses the ability to survive long term and mature into memory T cells that can provide long-term immunity. Understanding the signals that regulate the development of memory T cells is crucial to efforts to design vaccines capable of eliciting T cell-based immunity. CD4(+) T cells are essential in the formation of protective memory CD8(+) T cells following infection or immunization. However, until recently, the mechanisms by which CD4(+) T cells act to support memory CD8(+) T cell development following infection were unclear. Here, we discuss recent studies that provide insight into the multifaceted role of CD4(+) T cells in the regulation of memory CD8(+) T cell differentiation.

Figure 1. CD4⁺ T cell help to CD8⁺ T cells during immunization

a. Following immunization, naïve CD4⁺ T cells interact with and license cognate dendritic cells (DCs) through a CD40-dependent process. Licensed DCs express higher levels of MHC and costimulatory molecules and can recruit naïve CD8⁺ T to their cognate DC through secretion of the chemokines CCL3, 4, and 5. Licensed DCs also secrete IL-12 and IL-15, which increase expression of IL-2R (CD25) on CD8⁺ T cells and promote cell survival, respectively. Enhanced expression of CD25 facilitates the responsive of CD8⁺ T cells to IL-2 and promotes CD8⁺ T cell survival and their ability to proliferate upon secondary antigen encounter. Both CD4⁺ and CD8⁺ T cells act as sources of the IL-2, with CD4⁺ and CD8⁺ T cells in some settings also directly interacting through CD40:CD40L. b. Regulatory T (T_REG) cells can modulate the CD8⁺ T cell response following immunization by suppressing the maturation state of DCs, thereby limiting their ability to stimulate CD8⁺ T cells. By limiting chemokine secretion by DCs, T_REG cells can destabilize CD8⁺ T cell: DC interactions and accordingly promote the induction of high affinity effector and memory CD8⁺ T cells. T_REG cells also limit the sensing of IL-2 by CD8⁺ T cells by competing for available IL-2 and limiting the expression of CD25 by CD8⁺ T cells through control of DC secretion of IL-12.

Figure 2. T_REG cells promote memory CD8⁺ T cell maturation during viral infection

a. Following acute viral infection, T_REG cells expansion is initially suppressed due to the presence of high levels of type I IFNs. As type I IFNs wane, T_REG cell numbers increase with these cells adopting a more effector like phenotype marked by increased expression of IL-10 and CTLA-4. During the resolution phase of infection, T_REG cell-derived IL-10 acts to suppress the maturation state of DCs and limit their production of proinflammatory cytokines. T_REG cell expression of CTLA-4 acts in a similar manner through modulation of the CD28-CD80/86 signaling axis. Low levels of proinflammatory signals allow for the continued maturation of effector CD8⁺ T cells into functional memory CD8⁺ T cells. b. In the absence of T_REG cell-derived IL-10 and/or CTLA-4, DCs adopt a more mature phenotype and secrete higher levels of proinflammatory cytokines. The enhanced levels of proinflammatory cytokines are sensed by effector CD8⁺ T cells and drive these cells to adopt a more terminally differentiated phenotype, limiting their ability to proliferate and mediate protective immunity upon reencounter with the pathogen.

Figure 3. CD4⁺ T cell help to CD8⁺ T cell during mucosal infection

a. Following influenza virus infection, CD4⁺ T cells rapidly migrate from the draining lymph node (dLN) to the lung airways where they mediate the release of chemokines from epithelial cells via secretion of IFNγ. As CD8⁺ T cells move from the dLN to the lung parenchyma they upregulate CD69, likely due to exposure to inflammatory cytokines and T cell receptor signaling. These cells can then migrate towards the chemokine gradient surrounding the airway where they encounter TGFβ, which subsequently induces the expression of CD103 and suppression of the transcription factor T-bet, thereby promoting the establishment of a lung T_RM cell population. b. Following herpes simplex virus infection, CD4⁺ T cells migrate from the draining lymph node (dLN) to the female reproductive tract (FRT) where they mediate the release of chemokines from the infected tissue via secretion of IFNγ. CD4⁺ T cell-derived IFNγ is necessary for CD8⁺ T cells to migrate into the virally infected FRT. c. Following West Nile virus infection, CD8⁺ T cells primed in the dLN migrate to the central nervous system (CNS) parenchyma. T_REG cells also traffic to the CNS where they modulate the levels of TGFβ. T_REG cell-dependent control of TGFβ may modulate the expression of CD103 expression on CD8⁺ T cells and accordingly influence their ability to reside long-term in the brain.

Figure 4. Temporal model of CD4⁺ T cell help during viral infection

a. Following infection, antigen-specific T cells rapidly proliferate during priming and differentiate into cytotoxic T lymphocytes (CTLs) that mediate viral clearance. Most of these cells die over the next several weeks during the resolution phase of the response. Only a small percentage of effector T cells (5–10%) survive and further develop into functional mature memory CD8⁺ T cells. b. CD4⁺ T cells play distinct roles during these phases to regulate the development of CD8⁺ T cell memory. During the priming phase, CD4⁺ T cells license the entry of CD8⁺ T cell into mucosal tissues and promote viral clearance through the induction of a virus-specific effector CD4⁺ T cell and humoral response. Later in the resolution phase, T_REG cell-derived IL-10 facilitates the maturation of a mature memory CD8⁺ T cell population and can promote functional quiescence of memory cell through expression of the inhibitory receptor CTLA-4. T_REG cells may also modulate TGFβ levels in mucosal sites to promote CD103 expression and accordingly regulate T_RM cell development. During the memory phase, the CD4⁺ T cell-dependent immune response allows for continued suppression of viral outgrowth.