Recent Findings

1. We have contributed fundamental insights into how immune responses that begin in skin generate populations of memory T cells for host defense, including TRM. These latter cells are protective against infectious challenge and can mediate their effector function in the absence of antibody or circulating T cells. These findings, taken together, have led to the concept that skin immunization generate two compartments of immune memory, one in the tissues (TRM) and the other in secondary lymphoid tissue. We showed that the same naive T cell can differentiate into skin TRM and lymph node TCM in parallel, indicating that these two compartments of immune memory have overlapping T cell receptor repertoires. We also show that skin immunization generates populations of T cells that home to skin and lung. We have hypothesized that many T cell mediated tissue autoimmune disorders involve pathogenic TRM, and that successful treatment of these diseases will require dislodging TRM from tissue. Our recent paper demonstrated that TRM develop a requirement for internalization and -oxidation of exogenous free fatty acids for survival in peripheral tissues; this may be exploited therapeutically as the Achilles heel of TRM.

A. Jiang X, Clark RA, Liu L, Wagers A, Fuhlbrigge RC, Kupper TS. Skin infection generates non-migratory memory CD8+ T cells providing global skin immunity. Nature. 2012 Feb 29;483 (7388):227-31. PMCID: PMC3437663.

B. Gaide O, Emerson RO, Jiang X, Gulati N, Nizza S, Desmarais C, Robins R, Krueger JG, Clark RA, Kupper TS. Common clonal origin of central and resident T cells following skin immunization. Nat Med. 2015 May 11; 21:647-52. PMCID: PMC4632197

C. Pan Y, Tian T, Park CO, Lofftus SY, Mei S, Liu X, Luo C, O’Malley JT, Gehad A, Teague JE, Divito SJ, Fuhlbrigge R, Puigserver P, Krueger JG, Hotamisligil GS, Clark RA, Kupper TS. Survival of tissue resident memory T cells requires exogenous lipid uptake and metabolism. Nature. 2017 Mar 9; 543(7644):252-256. PMCID: PMC550905

D. Pan Y, Liu L, Tian T, Zhao J, Park CO, Lofftus SY, Stingley CA, Yan Y, Mei S, Liu X, Kupper TS. Epicutaneous Immunization with Modified Vaccinia Ankara Viral Vectors Generates Superior T Cell Immunity Against a Respiratory Viral Challenge. NPJ Vaccines. 2021 Jan 4;6(1):1. doi: 10.1038/s41541-020-00265-5.

2. My laboratory has contributed to the fundamental understanding the immunobiology of human skin homing T cells, from solving the structure(s) of the skin homing marker CLA, to the discovery of CLA positive skin resident T cells, to understanding that most CLA positive T cells are in fact TRM. Further studies characterized the role of different classes of skin T cells (including TRM), and the antigen specificity of TRM in skin and other tissues, indicating TRM responsiveness to tissue specific pathogens, and their role in human diseases like GVHD.

A. Fuhlbrigge RC, Kieffer JD, Armerding D, Kupper TS. Cutaneous lymphocyte antigen is a specialized form of PSGL-1 expressed on skin-homing T cells. Nature. 1997;389(6654):978-81.

B. Seneschal J, Clark RA, Gehad A, Baecher-Allan C, Kupper TS. Human epidermal langerhans cells maintain immune homeostasis in skin by activating skin resident regulatory T cells. Immunity. 2012 May 25;36(5):873-84. PMCID: PMC3716276

C. Watanabe R, Gehad A, Yang C, Scott L, Teague JE, Schlapbach CS, Elco C, Huang V, Matos TR, Kupper TS, Clark RA. Human skin is protected by four functionally and phenotypically discrete populations of resident and recirculating memory T cells. Sci Transl Med. 2015 Mar 18; 7(279): 279ra39. PMCID: PMC4425193

D. Divito SJ, Aasebo AT, Matos TR, Hsieh PC, Collin M, Elco CP, O’Malley JT, Bækkevold ES, Reims HM, Gedde-Dahl T, Hagerstrom M, Hilaire J, Lian JW, Milford EL, Pinkus GS, Ho VT, Soiffer RJ, Kim HT, Mihm Jr MC, Ritz J, Guleria I, Cutler CS, Clark R, Jahnsen FL, Kupper TS. Peripheral host T cells survive hematopoietic stem cell transplantation and promote graft-versus-host-disease. J Clin Invest. 2020 Jun 2;129965 PMID: 32516138

3. My laboratory was one of the first to describe keratinocyte cytokines as innate immune mediators. Prior to the 1980’s, keratinocytes were described as purely structural cells. Over the next 35+ years, we contributed fundamentally to identifying keratinocytes as major cytokine producers (particularly IL-1), described and IL-1/IL-1R axis in skin that generated multiple cytokine and chemokines, and validated these findings in vivo using transgenic mice. These were fundamental to the understanding of keratinocytes as important elements of the innate immune system, responsible for inflammation and the modification of adaptive immunity. This work was funded by a MERIT award (R37) from the NIAID.

A. Kupper TS, Ballard DW, Chua AO, McGuire JS, Flood PM, Horowitz MC, Langdon R, Lightfoot L, Gubler U. Human keratinocytes contain mRNA indistinguishable from monocyte interleukin 1 alpha and beta mRNA. Keratinocyte epidermal cell-derived thymocyte-activating factor is identical to interleukin 1. J Exp Med. 1986;164(6):2095-100.

B. Groves RW, Rauschmayr T, Nakamura K, Sarkar S, Williams IR, Kupper TS. Inflammatory and hyperproliferative skin disease in mice that express elevated levels of the IL-1 receptor (type I) on epidermal keratinocytes. Evidence that IL-1-inducible secondary cytokines produced by keratinocytes in vivo can cause skin disease. J Clin Invest. 1996;98(2):336-44.

C. Tian T, Jin MQ, Dubin K, King SL, Hoetzenecker W, Murphy GF, Chen CA, Kupper TS, Fuhlbrigge RC. IL-1R Type 1-Deficient Mice Demonstrate an Impaired Host Immune Response against Cutaneous Vaccinia Virus Infection. J Immunol. 2017 Jun 1;198(11):4341-4351. PMCID: PMC5506850

D. Tian T, Lofftus S, Pan Y, Stingley CA, King SL, Zhao J, Pan TY, Lock R, Marglous JW, Liu K, Widlund HR, Fuhlbrigge RC, Cichowski K, Kupper TS. IL1α antagonizes IL1β and promotes adaptive immune rejection of malignant tumors. Cancer Immunol Res. 2020 Mar 11. pii: canimm.0552.2019. [Epub ahead of print]. PMID: 32161110. NIHMSID: 1638519

4. My clinical work and translational laboratory work have both contributed to new insights into the biology of Cutaneous T Cell Lymphoma, including the loss of TCR repertoire complexity, the distinct cells of origin of mycosis fungoides and Sezary syndrome and the explanation for their responses to distinct therapies, initial discovery of the conserved expression of CCR4 in all forms of CTCL (anti-CCR4 is now a targeted CTCL therapy), and a presentation of genetic profiles of disease that predicted progression and outcome over a 12 year follow up period.

A. Campbell JJ, Clark RA, Watanabe R, Kupper TS. Sézary Syndrome and mycosis fungoides arise from distinct T cell subsets: a biologic rationale for their distinct clinical behaviors. Blood. 2010 Aug 5;116(5):767-771. PMCID: PMC2918332.

B. Clark RA, Watanabe R, Teague JE, Schlapbach C, Tawa MC, Adams N, Dorosario AA, Chaney KS, Cutler CS, LeBoeuf NR, Carter JB, Fisher DC, Kupper TS. Skin effector memory T cells do not recirculate and provide immune protection in alemtuzumab treated CTCL patients. Sci Transl Med. 2012 Jan 18; 4(117): 117ra7. PMCID: PMC3373186.

C. Kirsch I, Watanabe R, O’Malley J, Williamson D, Scott L, Elco C, Teague JE, Gehad A, Lowry L, LeBoeuf N, Krueger JG, Robins HS, Kupper TS*, Clark RA* (co-corresponding authors). TCR sequencing facilitates diagnosis and identifies mature T cells as the cell of origin in CTCL. Sci Transl Med. 2015 Oct 7; 7(308): 308ra158. PMCID: PMC4765389

D. de Masson A, O’Malley JT, Elco CP, Garcia SS, Divito SJ, Lowry EL, Tawa M, Fisher DC, Devlin PM, Teague JE, Leboeuf NR, Kirsch IR, Robins H, Clark RA, Kupper TS. High-throughput sequencing of the T cell receptor β gene identifies aggressive early-stage mycosis fungoides. Sci Transl Med. 2018 May 9;10(440). doi: 10.1126/scitranslmed.aar5894.

5. My laboratory has studied the role of T cells in antitumor immunity, principally in skin cancers, and the role of cytokines and T cells in modifying the development and enhancing the rejection of skin cancers This has resulted in patent applications on IL-9/Th-9 and cancer immunotherapy, and HTS of the TCR for melanoma prognosis. The role of tissue trafficking in T cell antitumor immunity and the role of TRM in tumor immunity are recent observations.

A. Clark RA, Huang SJ, Murphy GF, Mollet IG, Hijnen D, Muthukuru M, Schanbacher CF, Edwards V, Miller DMM, Kim JE, Lambert J, Kupper TS. Human squamous cell carcinomas evade the immune response by downregulation of vascular E-selectin and recruitment of regulatory T cells. J Exp Med. 2008 Sep 29;205(10):2221-34. PMCID: PMC2556796.

B. Purwar R, Schlapbach C, Xiao Sheng, Kang HS, Elyaman W, Jiang X, Jetten A, Khoury S, Fuhlbrigge RC, Kuchroo V, Clark RA, Kupper TS. Robust tumor immunity to melanoma mediated by interleukin 9. Nat Med. 2012 Aug; 18(8): 1248–1253. PMCID: PMC3518666

C. Aires DJ, Yoshida M, Richardson SK, Bai M, Liu L, Moreno R, Lazar AJF, Wick JA, Rich BE, Murphy G, Blumberg RS, Fuhlbrigge RC, Kupper TS. T-cell trafficking plays an essential role in tumor immunity. Lab Invest. 2019 Jan;99(1):85-92. PMID: 30353131. PMCID: PMC6309214

D. Pruessmann W, Rytlewski J, Wilmott J, Mihm MC, Attrill GH0, Dyring-Andersen B, Fields P, Zhan Q, Colebatch AJ, Ferguson PM, Thompson JF, Kallenbach K, Yusko E, Clark R, Robins H, Scolyer RA, Kupper TS. Molecular analysis of primary melanoma T cells identifies patients at risk for metastatic recurrence. Nature Cancer 1:197-209 (2020). NIHMSID: 1638625.