The Masopust laboratory studies T cell responses to viral and bacterial infections & candidate vaccines to help understand the development of immunological protection from re-infection. We employ a combination of flow cytometry, immunohistochemistry, intravital microscopy, cellular, and genetic approaches to observe and manipulate pathogen specific T cell responses. We are currently dedicated to elucidating the developmental cues that govern T cell migration to different anatomical locations, commitment to the memory lineage, and the contribution of memory T cell differentiation state and location to protection from re-infection. Memory T cells that reside within the respiratory, intestinal, and reproductive mucosa, which collectively represent the most common portals of pathogen entry or infection, are of particular interest. By understanding these issues, we hope to contribute to the development of better vaccination strategies and therapies for chronic diseases.
T Cell Immunosurveillance
T cells are tactile; antigen recognition on host cells requires cell-to-cell contact. How do T cells survey the enormous real estate (~40 trillion cells!) present in an adult human?
Major projects focus on resident memory T cell (TRM):
5) Marker identification and description of heterogeneity
6) Strategies for depletion
Prime Boost (Maximizing T Cell Memory)
Systemic heterologous prime boost vaccination with live replicating vectors results in:
1) Enhanced commitment of effectors to the memory lineage,
2) Preferential accumulation of extralymphoid memory T cells,
3) Enlargement of the memory CD8 T cell compartment, and
4) Preternatural levels of T cell memory.
Ongoing and available projects include:
1) Using het-prime-boost vaccination as a tool to probe memory fate decisions
2) Understanding memory precursor T cell metabolism
3) Testing the relationship between CD8 T cell quantity, quality, and location and protective immunity in various mouse models of infection.
4) Applying het-prime-boost to test the potential of CTL immunity to control or prevent chronic infection with the SIV rhesus macaque model of HIV-1 infection.
SIV CTL vaccine
CD8 T cells protect the host against intracellular infections, but are not effectively stimulated by many vaccines. Mounting evidence suggests that vaccines that establish protective memory CD8 T cells may be critical for protection against currently intractable diseases, including AIDS. We have designed a novel heterologous prime-boost vaccine that establishes preternatural levels of CD8 T cell immunity (JI 2006, Nature, 2009). We are currently exploiting this vaccine concept to test the potential of memory CD8 T cells to protect non-human primates against the SIV model of HIV infection.
Ongoing and available projects include:
1) Applying het-prime-boost to test the potential of CTL immunity to control or prevent chronic infection with the SIV rhesus macaque model of HIV-1 infection.
2) In situ examination of mucosal SIV pathogenesis and T cell responses in the naive and preternaturally immune primate host
3) Defining the relationship between memory T cell location and differentiation state in rhesus macaques
4) Characterizing basic resident memory T cells biology in primates
5) Testing sensing and alarm function of primate resident memory T cells
Laboratory mice live in abnormally hygienic specific pathogen free (SPF) barrier facilities. We showed that standard laboratory mouse husbandry has profound effects on the immune system and that environmental changes produce mice with immune systems closer to those of adult humans (Nature 2016). Unlike adult humans, laboratory mice lack effector-differentiated and mucosally distributed memory T cells. These cell populations were present in free-living barn populations of feral mice and pet store mice with diverse microbial experience, and were induced in laboratory mice after co-housing with pet store mice, suggesting that the environment is involved in the induction of these cells. Altering the living conditions of mice profoundly affected the cellular composition of the innate and adaptive immune systems, resulted in global changes in blood cell gene expression to patterns that more closely reflected the immune signatures of adult humans rather than neonates, altered resistance to infection, and influenced T-cell differentiation in response to a de novo viral infection.
We are using dirty mice as a tool to test very fundamental questions related to:
1) vaccine responses
2) aspects of allergy, autoimmunity, and the hygiene hypothesis
3) tumor biology
4) T cell immunosurveillance.
Repurposing antiviral immunity to fight tumors
Overcoming the immunosuppressive tumor microenvironment and getting adoptive cell and checkpoint blockade therapies to solid tumors remain major impediments to successful immunotherapy of cancer. Humans experience many viral infections. Once controlled, the host retains memory T cells throughout the entire body to sense reinfection or recrudescence. When that same virus is reencountered, these T cells sound an alarm that induces an immunostimulatory environment that activates and recruits many arms of the immune system. We found that human tumors, like healthy tissue, are surveyed by T cells specific for previously encountered viral infections. In mouse cancer models, local delivery of peptide (with no adjuvant) derived from a previously encountered viral infection, recapitulated the sensing and alarm T cell function: recruiting and activating both the innate and adaptive immune system. In fact, this approach also pulled chimeric antigen receptor (CAR) T cells to tumors. Viral peptide administration arrested rapidly growing and poorly immunogenic B16 melanoma tumors in vivo and this treatment synergized with anti-PD-L1 checkpoint blockade to eliminate measurable tumors, and prevented recurrence in mice. This project demonstrates that natural and existing antiviral immunity can be repurposed to fight tumors, without the need for adjuvant or reinfection nor the costly and difficult identification of tumor neo-antigens.
Current projects are defining mechanism, examining the potential to induce neo-antigen specific responses and control metastases, and exploring translation potential in humans.