IntroductionThe application of molecular technologies to identify proteins differentially expressed by transformed cells is providing large numbers of candidate antigens that can be potentially targeted to selectively eliminate tumor cells by cancer immunotherapy. 1,2 Efforts to vaccinate patients to such antigens have yielded some provocative results, but only a small subset of patients have demonstrated therapeutic responses, likely reflecting the many in vivo obstacles to generating potent responses to these proteins, particularly in patients with an established malignancy. 3 An alternative approach of isolating and expanding reactive T cells ex vivo followed by adoptive transfer into the patient circumvents many of these in vivo obstacles. Although this adoptive therapy approach has demonstrated significant clinical promise, 4 generating the large numbers of T cells required for adoptive therapy of cancer patients, particularly within the time constraints posed by progressive tumors, is often not feasible. Molecular technologies have now provided a means to more broadly capture the therapeutic potential of this treatment strategy. Genes encoding the ␣ and  chains of a T-cell receptor (TCR) can be isolated from a T cell reactive with the antigen of interest and restricted to a defined HLA allele, inserted into a shuttle expression vector, and then introduced into large numbers of T cells of individual patients sharing the restricting allele and the targeted protein. 5 This approach is already being pursued clinically, 6 and the goal is to establish a library of such defined TCR genes that could provide reagents for treating a diverse set of patients and diseases. Multiple virus-and tumor-reactive TCR genes have already been successfully isolated and re-expressed in T cells, including TCR genes with specificity for HLA*0201 (HLA-A2)-restricted epitopes from melanoma antigens 7-9 and HLA-A2-and HLA*2402-restricted WT1-derived epitopes. 10,11 The avidity of a T cell for its target reflects many factors, including the affinity of the TCR for its cognate antigen 12 and the level of TCR expression. [13][14][15] One difficulty with the TCR-transfer approach is that the TCR-transduced T cells are often of lower avidity than the parental T cell from which the TCR was derived due to failure to achieve wild-type levels of TCR expression, which likely contributed to the limited efficacy observed in the recently reported clinical trial pursuing this strategy. 6 Thus, the TCR chains introduced into T cells need to be initially selected for appropriate affinity 10,16 and inserted into vectors that can achieve and maintain high-level expression. 17 However, even if these criteria are met, the introduced exogenous ␣ and  chains can potentially assemble as pairs not only with each other but also with the endogenous TCR ␣ and  chains, thereby reducing the number of appropriately matched exogenous ␣TCR pairs at the cell surface and decreasing the achievable T-cell avidity. Such mismatched pairing poses a second substantive p...
CD8(+) T cell tolerance, although essential for preventing autoimmunity, poses substantial obstacles to eliciting immune responses to tumor antigens, which are generally overexpressed normal proteins. Development of effective strategies to overcome tolerance for clinical applications would benefit from elucidation of the immunologic mechanism(s) regulating T cell tolerance to self. To examine how tolerance is maintained in vivo, we engineered dual-T cell receptor (TCR) transgenic mice in which CD8(+) T cells recognize two distinct antigens: a foreign viral-protein and a tolerizing self-tumor protein. Encounter with peripheral self-antigen rendered dual-TCR T cells tolerant to self, but these cells responded normally through the virus-specific TCR. Moreover, proliferation induced by virus rescued function of tolerized self-tumor-reactive TCR, restoring anti-tumor activity. These studies demonstrate that peripheral CD8(+) T cell tolerance to self-proteins can be regulated at the level of the self-reactive TCR complex rather than by central cellular inactivation and suggest an alternate strategy to enhance adoptive T cell immunotherapy.
During responses against viruses and malignancies, naive CD8 T lymphocytes expand to form both short-lived effector cells and a population containing cells with the potential to be long-lived and participate in memory responses (memory precursor effector cells). The strength of antigenic, costimulatory, and cytokine signals during responses impacts the magnitude and type of CD8 populations formed. In vitro studies have revealed that the tyrosine phosphatase Src homology region 2 domain-containing phosphatase-1 (SHP-1) regulates signal transduction from receptors on T cells including the TCR, helping set the activation threshold, and therefore may shape responses of mature CD8 T cells in vivo. Analysis of CD8 T cells from motheaten mice, which are globally deficient in SHP-1, proved problematic due to cell-extrinsic effects of SHP-1 deficiency in non-T cells on CD8 T cells. Therefore, a conditional knockout of SHP-1 in mature single-positive T cells was developed to analyze cell-intrinsic consequences of complete and partial SHP-1 deficiency on CD8 T cell responses to acute viral infection. The results demonstrated that SHP-1 has disparate effects on subpopulations of responding cells, limiting the magnitude and quality of primary and secondary responses by reducing the number of short-lived effector cells generated without affecting the size of the memory precursor effector cell pool that leads to formation of long-term memory.
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