T-cell receptor signals direct the composition and function of the memory CD8+ T-cell pool

Abstract

IntroductionPathogen clearance requires that CD8 ϩ effector T cells produce inflammatory cytokines and develop cytolytic activity against infected target cells, after which a small number of memory cells survive that rapidly regain effector function in the event of rechallenge. During this process, a relatively homogeneous pool of naive CD8 ϩ T cells differentiates into heterogeneous pools of effector and memory CD8 ϩ T cells. 1 To initiate this differentiation program, naive T cells integrate signals from peptide:major histocompatibility complex (MHC) complexes, costimulatory molecules and cytokines. Manipulation of these signals influences the quality and kinetics of CD8 ϩ T-cell memory differentiation. [1][2][3][4] The molecular signals that orchestrate the function and diversification of effector and memory CD8 ϩ T-cell subsets downstream of these receptors are beginning to be elucidated and how T-cell receptor (TCR) signals affect CD8 ϩ T-cell effector function and fate choices is not fully understood. [5][6][7][8][9][10][11][12][13][14] The CD8 ϩ effector T-cell pool can be divided into terminally differentiated, short-lived KLRG-1 hi IL-7r␣ lo effector cells (SLECs) and less differentiated KLRG-1 lo IL-7r␣ hi memory precursor cells (MPECs). 3,[15][16][17] SLECs typically produce the effector cytokine interferon␥ (IFN␥) and may also coproduce tumor necrosis factor␣ (TNF␣) in response to antigen but only memory precursors can produce interleukin-2 (IL-2) in addition to IFN␥ and TNF␣. 17,18 The memory pool is a heterogeneous population that is commonly divided into effector memory (Tem) and central memory (Tcm) defined by surface markers including CD62L, which is expressed at higher levels on Tcm. 19,20 After contraction, the ratio of CD62L hi to CD62L lo memory cells increases, although the number of memory cells in the blood and spleen remains constant. While it is not clear whether this transition is the result of direct conversion of Tem to Tcm cells or preferential outgrowth of Tcm cells, it is clear that the rate of transition can be influenced by the strength and duration of initial antigenic stimulus. 1,8,21 Furthermore, the memory pool undergoes functional maturation, gaining enhanced proliferative capabilities. 22,23 The relative frequencies of memory subsets can vary depending on the nature or persistence of the inciting antigen and understanding how these factors influence memory development and maturation is important for predicting the quality of secondary responses. [24][25][26][27] While multiple cytokines and transcription factors are known to affect the balance between terminal differentiation and memory formation, the role of TCR signals has been more difficult to ascertain. 3,6,7,11,16,28,29 Adjustments in the quantity, quality, or duration of antigen presentation affect the magnitude of the primary response and the kinetics of differentiation, but do not appear to affect the functional quality of the cells. 3,5,12,14,21,28,[30][31][32][33] However, specific TCR signals can differential...

Loss of tonic T-cell receptor signals alters the generation but not the persistence of CD8+ memory T cells

“…5,[41][42][43] T-cell competition, duration, and strength of initial stimulation and persistent TCR:MHC interaction have both been shown to affect the kinetics of the shift from Tem to Tcm. 38,44,45 Similar to our findings, the shift from Tem to Tcm was previously shown to be accelerated after LCMV infection of mice harboring mutations at critical tyrosine residues of SLP-76, 46 which may be explained either by alterations in the initial priming or alterations in signal strength continuing well after the formation of the Tem compartment. Our results, however, clearly show that the early shift seen with the complete deletion of SLP-76 during the memory phase cannot be explained by differences in precursor frequency or signal strength of initial activation, because these events occur before deletion.…”

Diacylglycerol Kinase ζ (DGKζ) and Casitas b-Lineage Proto-Oncogene b–Deficient Mice Have Similar Functional Outcomes in T Cells but DGKζ-Deficient Mice Have Increased T Cell Activation and Tumor Clearance

“…Results demonstrated that mice deficient in DGKζ, Cbl-b or both molecules generate impaired memory T cell responses relative to WT mice, confirming previous reports with mice deficient in DGKζ (41) or Cbl-b (19). This implies that TCR signal strength is titrated to balance generation of effector responses with sustained memory (43, 44), such that decreased TCR signaling results in poor acute effector memory expansion, and enhanced TCR signaling results in diminished establishment of memory. The mechanistic basis of decreased memory establishment secondary to enhanced TCR signaling is an area of ongoing investigation.…”

Synchronizing transcriptional control of T cell metabolism and function

“…This 'focusing' of the T cell repertoire is due to the preferential expansion of T cell clones displaying TCRs with a high affinity for cognate antigen at the expense of low-affinity cells. This 'loss' of low-affinity T cell clones is mediated at least in part by apoptosis, proliferation cessation and premature development of memory T cells [84][85][86][87][88] . However, as discussed below, metabolic 'fitness' and competition for nutrients seem to be the major drivers of TCR repertoire focusing.…”