University of Minnesota
MICaB Graduate Program
MICaB Home | U of M Medical School | Graduate School

Unit's home page.

Current Students

Tijana Martinov

Thesis Advisor: Brian Fife

Year entered: 2013

Degrees received:
B.A., Macalester College, St. Paul, MN, 2012

Honors and Awards:

  • Best Poster (Graduate student category) at the Robert Hebbel Department of Medicine Research Day (May, 2014)
  • MICaB student service award (April 2016)


Type 1 Diabetes (T1D) is a CD4+ T cell-driven autoimmune condition that results in destruction of the pancreatic islets of Langerhans, and consequent loss of insulin production. Insulin itself is one of the main targets in human T1D patients and in non-obese diabetic (NOD) mice. With this in mind, our lab has developed insulin-peptide/MHC Class II tetramer reagents that allow us to track islet-reactive CD4+ T cells prior to and during disease progression in NOD mice. Using these reagents, we have been able to identify and phenotype insulin-specific CD4+ T cells, and show that the number of insulin-specific CD4+ T cells increases as NOD mice approach disease onset. Surprisingly, we were able to detect insulin-specific CD4+ T cells in the periphery of diabetes-resistant (B6.g7) mice. Having the reagents to track autoreactive cells also allowed us to investigate how they are regulated in health versus disease states. Programmed death-1 (PD-1) is a T cell inhibitory receptor, and deficiency or blockade of this receptor or its ligand (PD-L1) accelerates disease onset in NOD mice. We sought to determine how PD-1 blockade impacted the number and activation status of insulin-specific CD4+ T cells in NOD and B6.g7 strains. We demonstrated increased numbers of total and activated insulin-specific CD4+ T cells in the secondary lymphoid organs and pancreas of NOD mice following anti-PD-L1 treatment, as well as an increase in the number of activated insulin-specific CD4+ T cells in the pancreatic lymph nodes of B6.g7 mice. While insulin-specific CD4+ T cells became more antigen-experienced in B6.g7 mice after PD-1 blockade, they expressed less CXCR3, a pancreas homing receptor, compared to NOD counterparts. Importantly, PD-1 pathway blockade did not trigger islet inflammation or disease onset in B6.g7 mice. This suggests that other peripheral tolerance mechanisms are critical in B6.g7 mice. By identifying them, I hope to uncover those that are required, and harness them to prevent and cure diabetes.


  • Spanier J.A., D.R. Frederick, J.J. Taylor, J.R. Heffernan, D. Kotov, T. Martinov, K.C. Osum, J.L. Ruggiero, B.J. Rust, S.J. Landry, M.K. Jenkins, J.B. McLachlan, B.T. Fife. 2016. Efficient generation of monoclonal antibodies against peptide in the context of MHCII using magnetic enrichment. Nat Commun. 7:11804.
  • Martinov T., B.T. Fife. 2016. Commentary: Fractionated radiotherapy combined with PD-1 pathway blockade promotes CD8 T cell-mediated tumor clearance for the treatment of advanced malignancies. Ann Transl Med. 4:82.
  • Benck C.J., T. Martinov, B.T. Fife, D. Chatterjea. 2016. Isolation of infiltrating leukocytes from mouse skin using enzymatic digest and gradient separation. J Vis Exp. 107:e53638.
  • Martinov T., J.A. Spanier, K.E. Pauken, B.T. Fife. 2016. PD-1 pathway-mediated regulation of islet-specific CD4+ T cell subsets. Immunoendocrinology. 3:e1164.
  • Pauken, K.E.*, Nelson C.E.*, Martinov T.*, J. A. Spanier, J.R. Heffernan, N.L. Sahli, C. F. Quarnstrom, K.C. Osum, J.M. Schenkel, M.K. Jenkins, B.R. Blazar, V. Vezys and B.T. Fife. 2015. Cutting Edge: Identification of autoreactive CD4+ and CD8+ T cell subsets resistant to PD-1 pathway blockade. Journal of Immunology 194(8):3551-5.
    *authors contributed equally