Browsing by Subject "Receptors, Antigen, T-Cell"
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Item The Function of the TCR zeta zeta Module in T Cells(2005-04-29) Pitcher, Lisa Anne; van Oers, Nicolai S. C.The alpha beta T cell receptor complex (TCR) has the unique ability to discriminate and differentially respond to peptide/MHC ligands encountered on the surface of antigen presenting cells. The ligation of the TCR with peptide/MHC complexes is translated into intracellular signals through a conserved sequence motif, termed ITAM, or immunoreceptor tyrosine-based activation motif, which are present in one or more copies in the cytoplasmic portions of the TCR zeta and CD3 gamma, delta and epsilon chains. A distinctive feature of the TCR complex is that it contains ten ITAMs, in contrast to other antigen receptor complexes which contain two or four ITAMs. The ten TCR ITAMs are distributed as one in each CD3 chain and three in the TCR zeta subunit (TCR alpha beta epsilon delta epsilon gamma zeta zeta). It has been proposed that the TCR is comprised of two autonomous signaling modules, TCR zeta zeta and CD3 gamma epsilon/delta epsilon. Following receptor ligation, TCR zeta is the most heavily tyrosine-phosphorylated subunit of the TCR, developing into two stable intermediates of 21- and 23-kDa (p21 and p23). Based on the number of ITAMs it contributes, TCR zeta zeta was initially presumed to be the predominant signaling module in the TCR complex, with p21 and p23 being linked to virtually all aspects of T cell biology. To clearly define the functions of the TCR zeta zeta module, we generated a series of TCR zeta transgenic mice, with modified zeta molecules, that selectively express p21 alone, no p21 or p23, or no phospho-zeta intermediates. In a wild type or high affinity TCR system (P14), T cell development was completely normal in the TCR zeta transgenic lines. Surprisingly, when peripheral T cells were analyzed for their functionality in response to various stimuli, including peptide/MHC-, T cell mitogen- and superantigenic- stimulation, equivalent dose response curves were observed, regardless of phospho-zeta. Notably, these data also eliminated a possible inhibitory role for the partially phosphorylated p21 intermediate of TCR zeta. To more carefully examine the roles of p21 and p23, the TCR zeta transgenics were mated to a TCR transgenic line (HY) bearing T cells with a low affinity TCR. In this system, important roles for phospho-zeta during T cell selection were revealed. Specifically, TCR zeta ITAMs functioned additively during positive selection events. These selection events appear to be independent of traditional signaling pathways, as the signaling capacity of unselected T cells in the absence of all phospho-zeta was equivalent to T cells with wild-type TCR zeta subunits. These results imply that the CD3 gamma epsilon/delta epsilon module is the predominant signaling module in the TCR complex. Our studies also identified a unique role for p21 during negative selection events. The select expression of p21 in T cells attenuated negative selection of thymocytes, resulting in the generation of a population of potentially autoreactive cells. Based on these data, a revised model of TCR signal transmission is proposed. Within this model, the TCR zeta zeta and CD3 gamma epsilon/delta epsilon modules contribute both redundant and unique functions to T cells. The CD3 gamma epsilon/delta epsilon module is primarily responsible for classical TCR-mediated signaling pathways leading to T cell activation. The TCR zeta zeta and CD3 gamma epsilon/delta epsilon modules contribute redundant functions to thymocyte positive selection. These redundant functions are mediated by the ten TCR ITAMs. Phosphorylated intermediates of the TCR zeta zeta module also contribute to thymocyte positive selection, likely through alternative signaling pathways. In addition, the TCR zeta zeta module functions in a unique manner during thymocyte negative selection, with p21 attenuating negative selection of thymocytes. Furthermore, preliminary evidence suggests novel roles for the TCR zeta zeta module in the maintenance of peripheral T cells and in the adaptive immune response to bacterial pathogens.Item Modeling Tumor Neoantigens for Predicting Patients' Clinical Outcomes(December 2021) Lu, Tianshi; Hoshida, Yujin; Wang, Tao; Xiao, Guanghua; Ahn, Chul; Aguilera, Todd A.Tumor neoantigens are critical targets of the host antitumor immune response and their presence play an important role in affecting tumor progressions and immunotherapy treatment response. Neoantigens showed a lot of potential of being applied to clinical treatment. However, systematic study of neoantigens' impact on tumors and patients is still challenging due to the huge diversity of neoantigens, heterogeneity within tumors, and the model to study the pairing between neoantigen-MHC and T cells to identify the neoantigens that truly elicit T cell response. To study the impact of neoantigen-T cell interaction on tumorigenesis, I developed a Bayesian hierarchical model to infer the history of neoantigen-cytotoxic T cell interactions in tumors.Item Modulation of CD8+ T Cell Function by Beta2-Adrenergic Receptor Signaling(2017-05-31) Estrada, Leonardo Daniel; Malter, James; Farrar, J. David; Pfeiffer, Julie K.; Stowe, Ann; D'Orso, IvánThere is intimate crosstalk between the nervous system and the immune system. The nervous system can respond to immune system cues through afferent nerve endings. One effect of this response is the secretion of neurotransmitters in peripheral organs through efferent nerve endings. Primary and secondary immune organs are innervated predominantly by sympathetic nerve endings. The nerve termini are adrenergic and secrete norepinephrine upon stimulation, which can modulate immune cell function primarily through the beta2-adrenergic receptor (ADRB2). Our previous work has demonstrated that various subsets of CD8+ T cells have differential expression of the ADRB2 transcript. The role of ADRB2 signaling on the differentiation and acute effector functions of CD8+ T cells remains poorly understood. More importantly, its effect on CD8+ T cell memory development remains elusive. Therefore, I comprehensively addressed the role of ADRB2 signaling on different aspects of CD8+ T cell function. In the current body of work I demonstrate that intrinsic ADRB2 signaling downregulates CD8+ T cell acute effector functions, without affecting differentiation into effector cells. This is true with various forms of T cell receptor activation and with endogenous as well as pharmacological ADRB2 ligands. Furthermore, CD8+ T cell interferon-gamma secretion induced by innate cytokines was not affected. Finally, ADRB2-deficient CD8+ T cells fail to develop into memory cells after an in vivo viral infection. This effect is intrinsic to the ability of CD8+ T cells to signal through the ADRB2 as shown by bone marrow chimera experiments. The inability of ADRB2-deficient CD8+ T cells to develop into memory cells is accompanied by higher expression of several activation-related genes, as well as decreased expression of CD25 five days post-infection. However, restoration of CD25 expression in ADRB2-deficient cells with IL-2/anti-IL-2 treatment was unable to rescue memory development. Taken together, my results demonstrate for the first time that the sympathetic nervous system controls CD8+ T cell memory development through ADRB2 signaling on CD8+ T cells.Item Racing toward a cure for blood cancers with new CARs (CAR-T cell therapy)(2018-03-09) Anderson, Larry, Jr.Item The Role of the PTPH1-Family of Protein Tyrosine Phosphatases In T Cells(2007-12-18) Young, Jennifer Ann; van Oers, Nicolai S. C.The alpha beta T cell receptor complex activates intracellular signaling cascades by coupling to several families of protein tyrosine kinases and protein tyrosine phosphatases. Following T cell receptor interactions with cognate peptide/major histocompatibility complexes, Src-family protein tyrosine kinases phosphorylate two tyrosine residues in a conserved amino acid motif termed the immunoreceptor tyrosine-based activation motif. The immunoreceptor tyrosine-based activation motifs are present in one or more copies in the cytoplasmic tails of the T cell receptor invariant chains, CD3 gamma, delta, epsilon and zeta. In all T cell receptor signaling events, the immunoreceptor tyrosine-based activation motifs are transiently phosphorylated. We used a large-scale screen to identify protein tyrosine phosphatase candidates dephosphorylating the T cell receptor zeta immunoreceptor tyrosine-based activation motifs. PTPH1 was identified in this screen, but its endogenous expression was difficult to detect in T cells. Based on sequence homology, PTPN4 was also considered as a putative regulator of phospho-zeta. T cell receptor zeta was bound and dephosphorylated by PTPN4. Overexpression of wild-type PTPN4 inhibited T cell receptor-induced AP-1 and NFkappaB activation in T cells. The overexpression of a substrate-trapping derivative of PTPN4 significantly augmented NFkappaB activation. This finding demonstrates a role for PTPN4 in the regulation of the NFkappaB pathway. PTPN4 knock-out mice were generated to assess the role of this PTPase in lymphocytes. This is the first description of a PTPN4-deficient animal model. No major developmental defects were observed in the PTPN4 knock-out mice. However, PTPN4-deficient animals had altered peripheral effector/memory T cell populations. While early T cell activation and T cell receptor-induced signal transduction events were normal, peripheral T cells from PTPN4-null mice secreted elevated levels of IL-4, IL-5, and IL-13 in the absence of PTPN4. This suggests that PTPN4 has a selective role in regulating effector T cell differentiation. Taken together, both PTPH1 and PTPN4 may regulate T cell receptor zeta phosphorylation, but the unique functions of these two protein tyrosine phosphatases indicate non-overlapping substrates.Item Sympathetic Neural Control of Inflammation by ADRB2-Mediated IL-10 Secretion(2018-04-16) Agac, Didem; Hooper, Lora V.; Farrar, J. David; Gill, Michelle A.; Shiloh, MichaelThe nervous and immune systems reciprocally regulate their functions through the release of chemical messengers. Norepinephrine (NE), a neurotransmitter released by catecholaminergic nerve endings, allows the sympathetic nervous system to communicate with immune cells through adrenergic receptors (ADR). Although, the effects of adrenergic signaling has been studied in multiple cell types, its role in modulation of innate immune cells is relatively unknown. Here, I demonstrate a novel role for the beta2-ADR (ADRB2) in controlling inflammation. NE suppresses pro-inflammatory cytokine secretion from primary macrophages in response to multiple TLR agonists, and ADRB2 signaling enhances early induction of IL-10. In addition to its in vitro affects, I have shown that ADRB2 signaling controls inflammation in vivo. The in vivo role of this pathway was assessed by using an infection model, experimental colitis and LPS endotoxemia model. ADRB2-/- animals presented with splenomegaly and greater weight loss in infection and colitis, compared to ADRB2 sufficient animals, respectively. ADRB2-/- animals rapidly succumbed to a sub-lethal LPS challenge, which correlated with elevated serum levels of TNFα and reduced IL-10. Administration of exogenous IL-10 increased the survival of the ADRB2-/-. Additionally, the ADRB2-specific agonist salmeterol rescued wild-type animals from a lethal LPS challenge, which was reversed by neutralizing anti-IL-10 antibody. These observations suggest that ADRB2 signaling is critical for controlling inflammation through the rapid induction of IL-10. Transcriptome analysis revealed that the NR4A nuclear orphan family members were induced by NE. The presence of several putative NR4A binding sites within the IL-10 promoter suggests that these factors may directly regulate IL-10 expression in response to ADRB2 signaling. Additionally, mice that deficient in NR4A1 are susceptible in LPS endotoxemia model. These results suggest a novel pathway for control of inflammation via neuroendocrine cues. Understanding this pathway will provide new insights into how the nervous and immune systems communicate through ADRB2 signaling.Item The T cell receptor and human disease(1986-12-18) Capra, J. Donald