Background Information

I spent nearly 30 years of my career in industry, at various positions in four biotech companies (three start-up and one medium sized), and two large pharmaceutical companies. My focus has always been on the application of innovative discovery science to problems of human health. In the early part of my career, this focus was applied to drug discovery, but increasingly in later years, to developing methods to identify potential responders to existing drugs. I left industry and joined the Systems Immunology Division of BRI as a visiting scientist in September 2012. BRI offers the resources and access to clinical samples necessary for patient-centered approaches to biological research. I now run my own laboratory at BRI, developing cutting edge Systems Immunology approaches to biomarker, target and responder identification. My career in industry taught me the value of team approaches to science. We now work closely with a critical mass of immunologists, bioinformaticians, and programmers. Together, we have a fantastic opportunity to make basic discoveries that impact patient health.

Area of Research

Below are the main areas of research currently ongoing in the laboratory:

Determining the molecular basis for different rates of T1D progression. We are using cutting edge systems biology approaches to identify cellular and molecular markers in whole blood that characterize the preservation of beta cell function in newly diagnosed subjects with T1D (non-progressors). Our goal is to identify RNAseq and/or cellular signatures in whole blood that characterize non-progressor responses to different therapies and during natural history, and to determine whether these signatures are unique or treatment-specific.

Determining T cell ancestry and phenotypes from RNAseq analysis of individual antigen-specific T cells. We have developed a novel single-cell RNAseq approach for determining both TCR sequences and full transcriptome phenotypes from individual antigen-specific T cells. We are using this approach to elucidate clonotype/phenotype relationships of antigen-specific T cells in disease progression and response to therapy of subjects with autoimmune disease or cancer.

Elucidating immune processes in tumors that affect patient survival and response to therapy. We are developing novel transcript module approaches for analyzing tumor RNAseq profiles for pre-defined sets of co-regulated immune genes. We have shown that expression of immune genes within certain tumor types may be linked to patient survival. We are using this approach to identify new responder populations and targets for cancer immunotherapy.

Featured Publications

My career can be summarized by contributions to several major areas, shown below together with representative publications:

Most Recent Publications  

Herold KC, Bundy BN, Long SA, Bluestone JA, DiMeglio LA, Dufort MJ, Gitelman SE, Gottlieb PA, Krischer JP, Linsley PS, Marks JB, Moore W, Moran A, Rodriguez H, Russell WE, Schatz D, Skyler JS, Tsalikian E, Wherrett DK, Ziegler AG, Greenbaum CJ; Type 1 Diabetes TrialNet Study Group. An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes. N Engl J Med. 2019 Aug 15;381(7):603-613. doi: 10.1056/NEJMoa1902226. Epub 2019 Jun 9. PubMed PMID: 31180194.        

Linsley PS, Long SA. Enforcing the checkpoints: harnessing T-cell exhaustion for therapy of T1D. Curr Opin Endocrinol Diabetes Obes. 2019 Aug;26(4):213-218. doi: 10.1097/MED.0000000000000488. PubMed PMID: 31157632.

Linsley PS, Greenbaum CJ, Speake C, Long SA, Dufort MJ. B lymphocyte alterations accompany abatacept resistance in new-onset type 1 diabetes. JCI Insight. 2019 Feb 21;4(4). pii: 126136. doi: 10.1172/jci.insight.126136. eCollection 2019 Feb 21. PubMed PMID: 30830871.  PMCID: PMC6478438.

Dufort MJ, Greenbaum CJ, Speake C, Linsley PS. Cell type-specific immune phenotypes predict loss of insulin secretion in new-onset type 1 diabetes. JCI Insight. 2019 Feb 21;4(4). pii: 125556. doi: 10.1172/jci.insight.125556. eCollection 2019 Feb 21. PubMed PMID: 30830868. PMCID: PMC6478408.

Long SA, Thorpe J, Herold KC, Ehlers M, Sanda S, Lim N, Linsley PS, Nepom GT, Harris KM. Remodeling T cell compartments during anti-CD3 immunotherapy of type 1 diabetes. Cell Immunol. 2017 Sep;319:3-9. doi: 10.1016/j.cellimm.2017.07.007. Epub 2017 Aug 18. PubMed PMID: 28844471. PMCID: PMC5614459.

Cerosaletti K, Barahmand-Pour-Whitman F, Yang J, DeBerg HA, Dufort MJ, Murray SA, Israelsson E, Speake C, Gersuk VH, Eddy JA, Reijonen H, Greenbaum CJ, Kwok WW, Wambre E, Prlic M, Gottardo R, Nepom GT, Linsley PS. Single-Cell RNA Sequencing Reveals Expanded Clones of Islet Antigen-Reactive CD4⁺ T Cells in Peripheral Blood of Subjects with Type 1 Diabetes. J Immunol. 2017 Jul 1;199(1):323-335. doi: 10.4049/jimmunol.1700172. Epub 2017 May 31. PubMed PMID: 28566371. PMCID: PMC5499675.

SiRNAs And MicroRNAs Target Multiple MRNAs

Jackson AL, Bartz SR, Schelter J, Kobayashi SV, Burchard J, Mao M, Li B, Cavet G, Linsley PS. Expression profiling reveals off-target gene regulation by RNAi. Nat Biotechnol. 2003;21(6):635-7. doi: 10.1038/nbt831. PubMed PMID: 12754523.

Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, Castle J, Bartel DP, Linsley PS, Johnson JM. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature. 2005;433(7027):769-73. doi: 10.1038/nature03315. PubMed PMID: 15685193.

Using Molecular Profiling Techniques to Improving Drug Discovery

van 't Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, Peterse HL, van der Kooy K, Marton MJ, Witteveen AT, Schreiber GJ, Kerkhoven RM, Roberts C, Linsley PS, Bernards R, Friend SH. Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002;415(6871):530-6. doi: 10.1038/415530a. PubMed PMID: 11823860.

Discovery Of The Immunosuppressants, Abatacept And Belatacept 

Linsley PS, Brady W, Urnes M, Grosmaire LS, Damle NK, Ledbetter JA. CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med. 1991;174(3):561-9. PubMed PMID: 1714933; PMCID: 2118936.

Linsley PS, Wallace PM, Johnson J, Gibson MG, Greene JL, Ledbetter JA, Singh C, Tepper MA. Immunosuppression in vivo by a soluble form of the CTLA-4 T cell activation molecule. Science.1992;257(5071):792-5. PubMed PMID: 1496399.

Discovery Of The B7/CD28/CTLA-4 T Cell Costimulatory Axis

Linsley PS, Clark EA, Ledbetter JA. Pillars article: T-cell antigen CD28 mediates adhesion with B cells by interacting with activation antigen B7/BB-1. 1990. Proc. Natl. Acad. Sci. USA 87: 5031-5035. J Immunol. 2009;182(5):2559-63. PubMed PMID: 19234147.

List of Published Work

To view a full list of published work, please visit the National Center for Biotechnology Information library of medicine at pubmed.gov.