Relevant Degree Programs
Graduate Student Supervision
Doctoral Student Supervision (Jan 2008 - Mar 2019)
The cytokine Interleukin-7 (IL-7) is critical for T cell development and function. Mutations that block IL-7 signaling in humans cause severe combined immunodeficiency syndrome due to the failure of T cells to develop. Conversely, mutations that result in constitutive signaling through the IL-7 receptor can drive human leukemias, including Early Thymic Progenitor (ETP) acute lymphoblast leukemia. How IL-7 influences ETP development is still unclear since ETPs do not normally express IL-7Rα. We found that ETPs are highly dependent on and sensitive to changes in IL-7 signaling however, IL-7Rα expressing bone marrow progenitors are not. IL-7 does not regulate the survival or proliferation of ETPs, although it does at subsequent stages of T cell development. We hypothesize an instructive role of IL-7 signaling in the differentiation or migration of bone marrow precursors of ETPs that is distinct from its classic mechanisms regulating survival and proliferation.Adjuvant IL-7 has been shown to increase the quantity and quality of T cell responses to clear chronic viral infections, however, its physiological role in anti-viral T cells is unclear. We found that IL-7 signaling was required for efficient clearance of Influenza A virus (IAV) and protection from viral induced pathology. T cells require cell intrinsic IL-7 signaling for efficient primary CD4 and CD8 T cell responses to IAV. The requirement for IL-7 signaling in the anti-viral response, and the ability of exogenous IL-7 to boost T cell responses suggests that it may be clinically useful in therapy or vaccination against IAV. IAV remains an important global health challenge, with up to 10% of the global population infected annually. Current IAV vaccines do not generate universal cross-serotype immunity. T cell memory responses to IAV correlate with cross-serotype protection. Transcutaneous immunization has shown potential to induce memory T cell responses that can protect against infections at other mucosal sites, including the lung. We found that transcutaneous immunization generates a strong memory CD8 T cell response that can protect from challenge with IAV. Therefore, transcutaneous immunization may be a useful to produce cross-serotype IAV immunity.
The cytokine interleukin (IL)-7 is necessary for human T cell development and murine B and T lymphopoiesis. Mice lacking IL-7, either of its receptor components, the common γ chain (γc) or IL-7 receptor α (IL-7Rα), or essential intracellular signaling molecules are severely lymphopenic. Due to the developmental block in early T and B progenitors, the requirement for IL-7Rα signaling in later T and B cell stages has been difficult to evaluate. To address this question, we characterized lymphopoiesis in IL-7Rα449F mice harboring a single point mutationin IL-7Rα, where a key signaling residue (tyrosine 449) is mutated to phenylalanine (F).Biochemical analysis revealed that IL-7Rα Y449 is essential for activation of STAT5 and that there are both Y449-dependent and independent contributions to cell survival through regulation of Bcl-2 family members. IL-7Rα449F T and B cells are able to overcome the characteristic developmental block of IL-7Rα-/- mice and develop appreciable numbers of peripheral T and B cells. This finding permitted evaluation of peripheral T cell function. These experiments demonstrated that IL-7Rα Y449 signals are required for naïve T cell homeostasis, generation of a primary CD4 T cell response and for maintenance of memory CD8 T cells following Listeria monocytogenes infection. In contrast to expectations, the CD8 memory T cell maintenance defect does not appear to be a direct result of decreased Bcl-2 expression.Dysregulated cytokine signaling can also contribute to development and/or maintenance of leukemia and lymphoma. Through genetic analysis of two distinct oncogenes, we were able to show that the IL-7Rα449F mutation was sufficient to protect mice from IL-7 mediated T and B cell transformation and significantly delay the emergence of B cell lymphomas in the Eμ-myc mouse model of Burkitt’s lymphoma. Disruption of STAT5 activation appears to play a significant role in both models of tumor protection. Collectively, the data demonstrate that IL-7Rα signaling has both Y449-dependent and independent modalities that cooperate to ensure optimal B and T cell development and response to infection. Further, the data show that these signaling pathways can contribute to lymphomagenesis, and may be attractive targets for immunotherapeutics of IL-7 responsive tumors.
Recent Tri-Agency Grants
The following is a selection of grants for which the faculty member was principal investigator or co-investigator. Currently, the list only covers Canadian Tri-Agency grants from years 2013/14-2016/17 and excludes grants from any other agencies.
- IL-7 in lymphocyte development and immunity - Canadian Institutes of Health Research (CIHR) - Operating Grant (2013/2014)
- Regulation of T Cell Development, Function and Transformation by IL-7 - Canadian Institutes of Health Research (CIHR) - CIHR New Investigator (2013/2014)
- Interleukin-7 in the transition of bone marrow progenitors to the thymus. (2017)
Immunol Cell Biol.
- Emerging roles of T helper 17 and regulatory T cells in lung cancer progression and metastasis. (2016)
- F1000Prime Recommendation (2015)
- The Survival and Differentiation of Pro-B and Pre-B Cells in the Bone Marrow Is Dependent on IL-7Rα Tyr449 (2014)
Daniel T. Patton and Adam W. Plumb and Ninan Abraham
The Journal of Immunology 193 (7) 3446--3455
- Interleukin-7, but Not Thymic Stromal Lymphopoietin, Plays a Key Role in the T Cell Response to Influenza A Virus (2012)
Plumb, A.W. and Patton, D.T. and Seo, J.H. and Loveday, E.-K. and Jean, F. and Ziegler, S.F. and Abraham, N.
PLoS ONE 7 (11)
- Unusual timing of CD127 expression by mouse uterine natural killer cells (2012)
Zhang, J. and Chen, Z. and Fritz, J.H. and Rochman, Y. and Leonard, W.J. and Gommerman, J.L. and Plumb, A.W. and Abraham, N. and Anne Croy, B.
Journal of Leukocyte Biology 91 (3) 417-426
- Elevated IL-7 availability does not account for T cell proliferation in moderate lymphopenia (2011)
Osborne, L.C. and Patton, D.T. and Seo, J.H. and Abraham, N.
Journal of Immunology 186 (4) 1981-1988
- Mucosal memory CD8 + T cells are selected in the periphery by an MHC class i molecule (2011)
Huang, Y. and Park, Y. and Wang-Zhu, Y. and Larange, A. and Arens, R. and Bernardo, I. and Olivares-Villagómez, D. and Herndler-Brandstetter, D. and Abraham, N. and Grubeck-Loebenstein, B. and Schoenberger, S.P. and Van Kaer, L. and Kronenberg, M. and Teitell, M.A. and Cheroutre, H.
Nature Immunology 12 (11) 1086-1095
- CD45 regulates migration, proliferation, and progression of double negative 1 thymocytes (2010)
Lai, J.C.Y. and Wlodarska, M. and Liu, D.J. and Abraham, N. and Johnson, P.
Journal of Immunology 185 (4) 2059-2070
- Regulation of memory T cells by γc cytokines (2010)
Osborne, L.C. and Abraham, N.
Cytokine 50 (2) 105-113
- Selective ablation of the YxxM motif of IL-7Rα suppresses lymphomagenesis but maintains lymphocyte development (2010)
Osborne, L.C. and Duthie, K.A. and Seo, J.H. and Gascoyne, R.D. and Abraham, N.
Oncogene 29 (26) 3854-3864
- Impaired CD8 T cell memory and CD4 T cell primary responses in IL-7Rα mutant mice (2007)
Osborne, L.C. and Dhanji, S. and Snow, J.W. and Priatel, J.J. and Ma, M.C. and Miners, M.J. and Teh, H.-S. and Goldsmith, M.A. and Abraham, N.
Journal of Experimental Medicine 204 (3) 619-631
- Proteomics analysis of interleukin (IL)-7-induced signaling effectors shows selective changes in IL-7Rα 449F knock-in T cell progenitors (2007)
Duthie, K.A. and Osborne, L.C. and Foster, L.J. and Abraham, N.
Molecular and Cellular Proteomics 6 (10) 1700-1710
- RasGRP1 transmits prodifferentiation TCR signaling that is crucial for CD4 T cell development (2006)
Priatel, J.J. and Chen, X. and Dhanji, S. and Abraham, N. and Teh, H.-S.
Journal of Immunology 177 (3) 1470-1480
- Haploinsufficiency identifies STATS as a modifier of IL-7-induced lymphomas (2005)
Abraham, N. and Ma, M.C. and Snow, J.W. and Miners, M.J. and Herndier, B.G. and Goldsmith, M.A.
Oncogene 24 (33) 5252-5257
- Bone marrow transplant completely rescues hematolymphoid defects in STAT5A/5B-deficient mice (2003)
Snow, J.W. and Abraham, N. and Ma, M.C. and Goldsmith, M.A.
Experimental Hematology 31 (12) 1247-1252
- Loss of Tolerance and Autoimmunity Affecting Multiple Organs in STAT5A/5B-Deficient Mice (2003)
Snow, J.W. and Abraham, N. and Ma, M.C. and Herndier, B.G. and Pastuszak, A.W. and Goldsmith, M.A.
Journal of Immunology 171 (10) 5042-5050
- Transgenic bcl-2 is not sufficient to rescue all hematolymphoid defects in STAT5A/5B-deficient mice (2003)
Snow, J.W. and Abraham, N. and Ma, M.C. and Bronson, S.K. and Goldsmith, M.A.
Experimental Hematology 31 (12) 1253-1258
- STAT5 promotes multilineage hematolymphoid development in vivo through effects on early hematopoietic progenitor cells (2002)
Snow, J.W. and Abraham, N. and Ma, M.C. and Abbey, N.W. and Herndier, B. and Goldsmith, M.A.
Blood 99 (1) 95-101
- The murine double-stranded RNA-dependent protein kinase PKR is required for resistance to vesicular stomatitis virus (2000)
Stojdl, D.F. and Abraham, N. and Knowles, S. and Marius, R. and Brasey, A. and Lichty, B.D. and Brown, E.G. and Sonenberg, N. and Bell, J.C.
Journal of Virology 74 (20) 9580-9585
- Characterization of transgenic mice with targeted disruption of the catalytic domain of the double-stranded RNA-dependent protein kinase, PKR (1999)
Abraham, N. and Stojdl, D.F. and Duncan, P.I. and Méthot, N. and Ishii, T. and Dubé, M. and Vanderhyden, B.C. and Atkins, H.L. and Gray, D.A. and McBurney, M.W. and Koromilas, A.E. and Brown, E.G. and Sonenberg, N. and Bell, J.C.
Journal of Biological Chemistry 274 (9) 5953-5962
- Double-stranded-RNA-activated protein kinase PKR enhances transcriptional activation by tumor suppressor p53 (1999)
Cuddihy, A.R. and Li, S. and Tam, N.W.N. and Wong, A.H.-T. and Taya, Y. and Abraham, N. and Bell, J.C. and Koromilas, A.E.
Molecular and Cellular Biology 19 (4) 2475-2484
- The murine PKR tumor suppressor gene is rearranged in a lymphocytic leukemia (1998)
Abraham, N. and Jaramillo, M.L. and Duncan, P.I. and Méthot, N. and Icely, P.L. and Stojdl, D.F. and Barber, G.N. and Bell, J.C.
Experimental Cell Research 244 (2) 394-404
- The interferon system: A review with emphasis on the role of PKR in growth control (1995)
Jaramillo, M.L. and Abraham, N. and Bell, J.C.
Cancer Investigation 13 (3) 327-338
- Dual specificity kinases - A new family of signal transducers (1994)
Douville, E. and Duncan, P. and Abraham, N. and Bell, J.C.
Cancer and Metastasis Reviews 13 (1) 1-7
- Structural requirements for enhancement of T-cell responsiveness by the lymphocyte-specific tyrosine protein kinase p56(lck) (1992)
Caron, L. and Abraham, N. and Pawson, T. and Veillette, A.
Molecular and Cellular Biology 12 (6) 2720-2729
- Enhancement of T-cell responsiveness by the lymphocyte-specific tyrosine protein kinase p56(lck) (1991)
Abraham, N. and Miceli, M.C. and Parnes, J.R. and Veillette, A.
Nature 350 (6313) 62-66
- The lymphocyte-specific tyrosine protein kinase p56(lck) (1991)
Abraham, N. and Veillette, A.
Cancer Investigation 9 (4) 455-463
- The lymphocyte-specific tyrosine protein kinase p56lck (1991)
Veillette, A. and Abraham, N. and Caron, L. and Davidson, D.
Seminars in Immunology 3 (3) 143-152
- Tyrosine phosphorylation of GAP and GAP-associated proteins in lymphoid and fibroblast cells expressing lck (1991)
Ellis, C. and Liu, X. and Anderson, D. and Abraham, N. and Veillette, A. and Pawson, T.
Oncogene 6 (6) 895-901
- Activation of p56(lck) through mutation of a regulatory carboxy-terminal tyrosine residue requires intact sites of autophosphorylation and myristylation (1990)
Abraham, N. and Veillette, A.
Molecular and Cellular Biology 10 (10) 5197-5206