The Jameson lab primarily focuses on the homeostasis, trafficking, and differentiation of CD8+ T cells, and how these can be regulated to promote beneficial responses and limit immunopathology.
Dr. Jameson studies the regulation of CD8 T cell development, homeostasis, and function. A major focus has been the factors, including cytokines, that induce and maintain protective memory CD8 T cells, capable of efficient control of pathogens and tumors. A related interest is on T cell trafficking, including the cues that determine whether memory T cells patrol around the body (recirculating) or remain in tissues (resident). In particular, we explore the regulation of T cell trafficking by KLF2 and related transcription factors, testing how manipulation of T cell migration can be used to tailor T cell function. Other studies investigate the role of the innate immune "danger" signal receptor P2RX7, which we showed is also critical for supporting survival and metabolic fitness of long-lived memory CD8+ T cells; analysis of non-deletional mechanisms of immunological tolerance as a means to avoid autoimmunity; and work on the immune response to pathogens and allergens in mice with normal microbial experience (also called 'dirty' mice), which we showed are a more faithful model of the adult human immune system.
The T-cell component of the adaptive immune system is proving to be highly complex, with many T-cell subcategories being identified as investigative tools such as flow cytometry and transgenic technologies become more sophisticated. The Jameson lab primarily focuses on the mechanisms that control development, homeostasis, and trafficking of naive and memory CD8+ T cells. As well as the regulation of protective immunity versus immunopathology in T cell responses. Physiological role of self-recognition by the T cell receptor : Recognition of "self" peptide/MHC molecules by the T cell receptor (TCR) is usually considered from the perspective of autoimmunity – but every T cell has to recognize self-ligands (in low affinity interactions) in order to mature in the thymus. We've investigated how these kinds of TCR interactions promote mature T cell survival and can even drive differentiation into a memory-like population (in conjunction with cytokine receptor stimulation). Furthermore, we discovered that the "strength" of the TCR encounter with self-peptide/MHC dictates a T cell's reactivity to foreign antigens: naïve CD8+ T cells with features of greater "self-awareness" showed stronger responses to pathogens. This implies a degree of self-reactivity is beneficial for normal immune function. We're also investigating how CD8+ T cell tolerance to self-peptide/MHC molecules is controlled. In a model we've investigated, involving tolerance to a melanocyte antigen, few self-specific T cells are eliminated during thymic development, and these cells are capable of a robust response to the self-antigen following immunization – however, these cells are poor at inducing immunopathology, suggesting tolerance is narrowly tailored to prevent overt tissue damage. We continue to explore how interactions with self- peptide/MHC ligands are critical to support T cell development, homeostasis and functional reactivity – and to understand how such interactions become unregulated, leading to autoimmunity. Role and regulation of the CD8 coreceptor : The CD8 co-receptor is critical for coordinated binding of the TCR to Class I MHC molecules. We've shown that the strength of the CD8-Class I MHC interaction changes during T cell development, such that optimal interactions occur in developing thymocytes that also show a heightened TCR sensitivity for self-peptide/MHC, which is required for their maturation. We found that this developmental regulation of CD8-Class I MHC binding is regulated, at least in part, by changes in cell surface glycosylation as T cell mature. We also showed that CD8 expression itself is dynamically regulated following T cell activation, so that stimulated CD8+ T cells are temporarily "detuned" after activation, resulting in altered states of ligand recognition. Together, these findings suggest ways in which we might improve desirable CD8+ T cell responses (such as tumor immunotherapy) by enhancing CD8 binding to Class I MHC ligands. CD8+T cell memory: A primary focus of the Jameson lab is CD8+ T cell memory, in all its varied forms. While memory cells are typically considered to arise following an immune response to foreign antigens, we discovered that homeostatic processes, involving TCR interactions with normal self-peptide/MHC ligands and exposure to homeostatic cytokines such as IL-7 and IL-15, lead "naïve" CD8+ T cells to acquire functional characteristics of "true" memory cells. We and others showed that such "virtual" memory cells arise physiologically in normal mice (and resemble a population in humans) and that these cells participate in the response to pathogens, exhibiting a distinct differentiation program from naïve cells. How these cells contribute to immune readiness toward new infections is an active area of interest. We also study conventional memory cells, with a special focus on how distinct "subsets" of memory cells offer distinct mechanisms of protective immunity. For example, some memory CD8+ T cells are embedded in tissues and do not enter the circulation during normal homeostasis ("resident memory" T cells, TRM), while others appear to primarily patrol the blood vasculature, without routinely entering tissues. We are especially interested in what regulates the decision of memory precursors to become distinct memory cell subsets. We recently showed that a purinergic receptor called P2RX7 is critical for generation of CD8+ TRM and "central" memory cells but is largely dispensable for other memory subsets. This was intriguing because the best studied role of P2RX7 is as a receptor for "danger" signals, as a way of activating the innate immune cells to current tissue damage – our data show that P2RX7 has quite distinct role in supporting the metabolic fitness of long-term memory CD8+ T cells. We're currently exploring how P2RX7 and related molecules control CD8+ T cell tumor immunotherapy. Other studies have focused on molecules that are associated with resident versus recirculating cells - distinguishing proteins that are valuable markers but play a limited functional role (such as CD69) from others that have actual functional significance (such as ICOS and S1PR1). Control of lymphocyte trafficking and differentiation by KLF2 : We began working on the transcription factor Kruppel-like factor 2 (KLF2, also called LKLF) because it was thought to be a key player in regulating naïve T cell quiescence. Instead, we found that a primary role of KLF2 is to regulate T cell trafficking – two prominent targets of KLF2 being CD62L (L-selectin) and S1PR1 (a receptor for sphingosine-1-phosphate, essential for lymphocyte egress into blood and lymph). This led to an entirely new understanding of both the function of KLF2 and, more broadly, the mechanisms that control thymocyte egress to the periphery and T cell recirculation. We went on to show that decreased expression of KLF2 (and its target S1PR1) is critical for generating CD8+ TRM in non-lymphoid tissues, but also is critical for generating differentiation of CD4+ T cells into "follicular helper" T cells TFH in the germinal center of lymphoid tissues. These and other intriguing parallels indicate similar regulation modules are at play in controlling localization versus dissemination of T cells (and possibly other lymphocytes) through regulation of KLF2 and other KLF transcription factors. Evaluation of mice with normalized immunological experience : In a long-term collaboration with the Masopust and Hamilton-Hart labs, we've studied how a more physiological exposure to natural mouse pathogens and commensal microbes impacts the immune system in laboratory mice – and the validity of mice as a model for the adult human immune system. To do so we examined mice that were not maintained under typical Specific Pathogen Free (SPF) housing conditions but were exposed to natural microbe transmission from mice purchased from a pet store. This results in widespread immune activation in the inbred mice and substantial and sustained changes in numerous immunological parameters. We showed that these so-called "dirty mice" had characteristics that a more faithful reflection of the immune system in adult humans (while conventional SPF mice more accurately reflect the immune system in neonatal humans). We've investigated how microbial experience influences the response to novel infections, immunopathology and the response to allergens, among other immune parameters. These studies show widespread changes in the nature of many (but not all) immune responses, suggesting exposure to microbes causes permanent remodeling of the immune system, producing a "new normal" baseline of immune readiness.
For a full list of publications: Link here
CoAching CD8(+) T cells for tumor immunotherapy-the pantothenate way. Kelekar A and Jameson SC. Cell Metab 2021,33(12), 2305-2306. https://doi.org/10.1016/j.cmet.2021.11.009
Senolytics reduce coronavirus-related mortality in old mice. Christina D. Camell, Matthew J. Yousefzadeh, Yi Zhu, Larissa G. P. Langhi Prata, Matthew A. Huggins, Mark Pierson, Lei Zhang, Ryan D. O’Kelly, Tamar Pirtskhalava, Pengcheng Xun, Keisuke Ejima, Ailing Xue, Utkarsh Tripathi, Jair Machado Espindola-Netto, Nino Giorgadze, Elizabeth J. Atkinson, Christina L. Inman, Kurt O. Johnson, Stephanie H. Cholensky , Timothy W. Carlson, Nathan K. LeBrasseur, Sundeep Khosla, M. Gerard O’Sullivan, David B. Allison, Stephen C. Jameson, Alexander Meves, Ming Li, Y. S. Prakash, Sergio E. Chiarella, Sara E. Hamilton, Tamara Tchkonia, Laura J. Niedernhofer, James L. Kirkland, and Paul D. Robbins. Science, 08 Jun 2021.doi: 10.1126/science.abe4832
Classical MHC expression by DP thymocytes impairs the selection of non-classical MHC restricted innate-like T cells. Georgiev, H., Peng, C., Huggins, M.A., Jameson S. C., Hogquist, K.A. Nat Commun 12, 2308 (2021). https://doi.org/10.1038/s41467-021-22589-z
T Cell Memory: Understanding COVID-19.
Jarjour NN, Masopust D, Jameson SC. Immunity. 2021 Jan 12;54(1):14-18. doi: 10.1016/j.immuni.2020.12.009. Epub 2020 Dec 19. PMID: 33406391
The Naming of Memory T-Cell Subsets.
Jameson SC.Cold Spring Harb Perspect Biol. 2021 Jan 4;13(1):a037788. doi: 10.1101/cshperspect.a037788. PMID: 33229439
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