CD8+ memory T cells (CTL) can confer lifelong protection from a wide variety of viral and bacterial pathogens, and can mediate the eradication of tumors. Conversely, CTL cause pathogenic autoimmunity and undesirable rejection of tissue grafts when not properly regulated. A mechanistic understanding of how memory CTL are established and maintained would allow for new approaches to inducing antigen-specific activation versus tolerance according to a patient's clinical need. The provision of help by CD4+ T lymphocytes (TH) to CTL represents an important control point in this pathway as it involves the transmission of signals that are critical for their functional activation and development into memory cells. Our ongoing studies have yielded key insights in this pathway by showing TH acts early during CTL priming to establish a program of development which allows them to undergo secondary expansion and avoid of TRAIL-mediated activation-induced cell death (AICD) upon reencounter with antigen. More recently, we have shown that the transcriptional regulator Nab2 controls the induction of TRAIL in helped versus helpless CTL. Furthermore, we have been able to prove an entirely new model of T help for CTL that reconciles differences implicit in the two previous models by showing that CD40-mediated APC activation by TH endows CTL with the capacity to produce their own autocrine IL-2. Taken together, the observations lay the foundation for a new exploration of the mechanisms underlying the generation of CTL memory and offer new possibilities for their strategic manipulation. The goal of this research is to complete our understanding of the cellular and molecular mechanism through which TH is transmitted to CTL. Outstanding questions in this regard include 1) identification of the signals provided by TH-activated APC to CTL that constitute the help message leading to memory functionality, 2) understanding the conditions under which autocrine versus paracrine (i.e. CD4-produced) IL-2 is involved in CTL responses, and 3) achieving a mechanistic understanding of how certain immunogens generate TH-independent memory CTL. We will examine each of these areas through the functional, phenotypic, and molecular analysis of primary CTL using in vivo models of infection and immunity. Our central hypothesis in these studies is that TH-activated APC transmit specific and inducible signals via the CD70-CD27 pathway to generate memory CTL, that paracrine (TH-produced) IL-2 can be important for responses against poorly immunogenic antigens, and that TH-independent CTL are produced by direct and indirect activation of APC by inflammatory stimuli, leading to transmission of the same distal signals as those achieved by TH through CD40-activation. Successful completion of this project will place the generation of memory CTL on a firm experimental and theoretical foundation and allow a greater potential for it's manipulation in health and disease.

Public Health Relevance

This project proposes a new mechanism through which CD4+ T cells participate in the priming of memory CD8+ T cells, and will establish the cellular and molecular pathways through which this occurs. Additionally, it will define the contribution of paracrine versus autocrine IL-2 production by CD4+ and CD8+ T cells, respectively, and how this shapes the repertoire emerging from a given immunogenic challenge.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Transplantation, Tolerance, and Tumor Immunology Study Section (TTT)
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Kelly, Halonna R
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La Jolla Institute
La Jolla
United States
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Polonskaya, Zinaida; Deng, Shenglou; Sarkar, Anita et al. (2017) T cells control the generation of nanomolar-affinity anti-glycan antibodies. J Clin Invest 127:1491-1504
Hope, Jennifer L; Pulendran, Bali; Schoenberger, Stephen P et al. (2016) 1st International Conference on Human &Translational Immunology. Nat Immunol 18:1-4
Romero, Pedro; Banchereau, Jacques; Bhardwaj, Nina et al. (2016) The Human Vaccines Project: A roadmap for cancer vaccine development. Sci Transl Med 8:334ps9
Kreiter, Sebastian; Vormehr, Mathias; van de Roemer, Niels et al. (2015) Mutant MHC class II epitopes drive therapeutic immune responses to cancer. Nature 520:692-6
Miller, Aaron M; Schoenberger, Stephen P (2015) Notch signaling maintains T cell memories. Nat Med 21:16-8
Rozanski, Cheryl H; Utley, Adam; Carlson, Louise M et al. (2015) CD28 Promotes Plasma Cell Survival, Sustained Antibody Responses, and BLIMP-1 Upregulation through Its Distal PYAP Proline Motif. J Immunol 194:4717-28
Togher, Susan; Larange, Alexandre; Schoenberger, Stephen P et al. (2015) FoxO3 is a negative regulator of primary CD8+ T-cell expansion but not of memory formation. Immunol Cell Biol 93:120-5