SH2 domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76) nucleates a signaling organic critical for T-cell receptor (TCR) transmission propagation. regain effector function in the event of rechallenge. During this process, a relatively homogeneous pool of naive CD8+ T cells differentiates into heterogeneous pools of effector and memory CD8+ 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+ T-cell memory differentiation.1C4 The molecular signals that orchestrate the function and diversification of effector and memory CD8+ T-cell subsets downstream of these receptors are beginning to be elucidated and how T-cell receptor (TCR) signals affect CD8+ T-cell effector function and fate choices is not fully understood.5C14 The CD8+ effector T-cell pool can be divided into terminally differentiated, short-lived KLRG-1hiIL-7rlo effector cells (SLECs) and less differentiated KLRG-1loIL-7rhi memory precursor cells (MPECs).3,15C17 SLECs typically produce the effector 477-57-6 manufacture 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 CD62Lhi to CD62Llo memory cells 477-57-6 manufacture increases, although the number of memory cells in the blood and spleen remains constant. While it is usually not obvious whether this transition is usually the result of direct conversion of Tem to Tcm cells or preferential outgrowth of Tcm cells, it is usually obvious that the rate of transition can 477-57-6 manufacture be affected by the strength and period of initial antigenic stimulation.1,8,21 Furthermore, the memory pool undergoes functional maturation, gaining enhanced proliferative capabilities.22,23 The family member frequencies of memory subsets can vary depending on the nature or perseverance of the inciting antigen and understanding how these factors influence memory development and maturation is usually important for predicting the quality of secondary responses.24C27 While multiple cytokines and transcription factors are known to affect 477-57-6 manufacture the balance between airport terminal differentiation and memory formation, the role of TCR signals has been more hard to ascertain.3,6,7,11,16,28,29 Adjustments in the quantity, quality, or duration of antigen presentation affect the degree of the primary response and the kinetics of differentiation, but do not appear to affect the functional quality of the cells.3,5,12,14,21,28,30C33 However, specific TCR signals can differentially affect the long-term fate of CD8+ T cells, as T cells with defective nuclear factor B activation undergo normal main expansion and airport terminal differentiation but not memory development.13 Here we explore the role of TCR signals in the differentiation, heterogeneity, and function of CD8+ effector and memory T cells using 2 strains of genomic knock-in (KI) mice that express mutations within the SH2 domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76) protein.34 SLP-76 is a critical adaptor that links early TCR-induced phosphorylation events to multiple downstream effector molecules.35 We show that T cells from KI mice containing tyrosine to phenylalanine mutations at either residue 145 IMPG1 antibody (Y145F) or residues 112 and 128 (Y112/128F) exhibit defects in proximal signaling downstream of the TCR and that these defects are more pronounced in the Y145F mice compared with the Y112/128F mice. After contamination with the Armstrong strain of lymphocytic choriomeningitis computer virus (LCMV), SLP-76 mutant CD8+ T cells undergo main growth to the extent of wild-type (WT) cells despite striking defects in cytokine effector function. Furthermore, the KI CD8+ pools are skewed toward a memory phenotype. Quantitative differences.