We study a patient with the human papilloma virus (HPV)-2-driven "tree-man" phenotype and two relatives with unusually severe HPV4-driven warts. The giant horns form an HPV-2-driven multifocal benign epithelial tumor overexpressing viral oncogenes in the epidermis basal layer. The patients are unexpectedly homozygous for a private CD28 variant. They have no detectable CD28 on their T cells, with the exception of a small contingent of revertant memory CD4(+) T cells. T cell development is barely affected, and T cells respond to CD3 and CD2, but not CD28, costimulation. Although the patients do not display HPV-2- and HPV-4-reactive CD4(+) T cells in vitro, they make antibodies specific for both viruses in vivo. CD28-deficient mice are susceptible to cutaneous infections with the mouse papillomavirus MmuPV1. The control of HPV-2 and HPV-4 in keratinocytes is dependent on the T cell CD28 co-activation pathway. Surprisingly, human CD28-dependent T cell responses are largely redundant for protective immunity.

Author Info: (1) University of Paris, Imagine Institute, INSERM U1163, 75015 Paris, France; The Rockefeller University, New York, NY 10065, USA. Electronic address: vivien.beziat@inserm.fr. (2)

Author Info: (1) University of Paris, Imagine Institute, INSERM U1163, 75015 Paris, France; The Rockefeller University, New York, NY 10065, USA. Electronic address: vivien.beziat@inserm.fr. (2) The Rockefeller University, New York, NY 10065, USA. (3) Pennsylvania State University College of Medicine, Hershey, PA 17033, USA. (4) University of Paris, Imagine Institute, INSERM U1163, 75015 Paris, France. (5) University of Paris, Imagine Institute, INSERM U1163, 75015 Paris, France. (6) McGill University, Montreal, QC H3A 0G1, Canada. (7) University of Cambridge, Cambridge CB2 1QP, UK. (8) University of Paris, Imagine Institute, INSERM U1163, 75015 Paris, France. (9) Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia; St. Vincent's Clinical School, UNSW Sydney, Sydney, NSW 2052, Australia. (10) Isfahan University of Medical Sciences, AIRC, Isfahan 81746-73461, Iran. (11) Zanjan University of Medical Sciences, Zanjan 45139-56184, Iran. (12) Stanford University Medical School, Stanford, CA 94305, USA. (13) Institute for Research in Fundamental Sciences (IPM), Tehran 19395-5746, Iran. (14) National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA. (15) Institute of Innovative Research, Tokyo Institute of Technology, Yokohama 226-8501, Japan. (16) Sidra Medicine, Doha, Qatar. (17) Sidra Medicine, Doha, Qatar. (18) Sidra Medicine, Doha, Qatar. (19) German Cancer Research Center, 69120 Heidelberg, Germany. (20) Sidra Medicine, Doha, Qatar. (21) University of Paris, Imagine Institute, INSERM U1163, 75015 Paris, France. (22) The Rockefeller University, New York, NY 10065, USA. (23) Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia; St. Vincent's Clinical School, UNSW Sydney, Sydney, NSW 2052, Australia. (24) University of Paris, Imagine Institute, INSERM U1163, 75015 Paris, France; Necker Hospital for Sick Children, AP-HP, 75015 Paris, France. (25) Pennsylvania State University College of Medicine, Hershey, PA 17033, USA. (26) Pennsylvania State University College of Medicine, Hershey, PA 17033, USA. (27) Pennsylvania State University College of Medicine, Hershey, PA 17033, USA. (28) Sidra Medicine, Doha, Qatar. (29) Sidra Medicine, Doha, Qatar. (30) Zahedan University of Medical Sciences, 054 Zahedan, Iran. (31) University of Leuven, 3000 Leuven, Belgium. (32) University of Paris, Imagine Institute, INSERM U1163, 75015 Paris, France. (33) Necker Hospital for Sick Children, AP-HP, 75015 Paris, France. (34) Necker Hospital for Sick Children, AP-HP, 75015 Paris, France. (35) Papillomavirus National Reference Center, Besanon Hospital, 25030 Besanon, France. (36) University of Paris, Imagine Institute, INSERM U1163, 75015 Paris, France. (37) University of Paris, Imagine Institute, INSERM U1163, 75015 Paris, France. (38) University of Paris, Imagine Institute, INSERM U1163, 75015 Paris, France. (39) Papillomavirus National Reference Center, Besanon Hospital, 25030 Besanon, France. (40) Thomas Jefferson University, Philadelphia, PA 19107, USA. (41) Thomas Jefferson University, Philadelphia, PA 19107, USA. (42) Thomas Jefferson University, Philadelphia, PA 19107, USA. (43) Thomas Jefferson University, Philadelphia, PA 19107, USA. (44) Foch Hospital, 92150 Suresnes, France. (45) Dr. Shahrooei Lab, Ahvaz, Iran. (46) University of Paris, Imagine Institute, INSERM U1163, 75015 Paris, France. (47) University of Southern California, Los Angeles, CA 90033, USA. (48) Cochin University Hospital, AP-HP, 75014 Paris, France. (49) Pennsylvania State University College of Medicine, Hershey, PA 17033, USA. (50) The Rockefeller University, New York, NY 10065, USA. (51) University of Paris, Imagine Institute, INSERM U1163, 75015 Paris, France. (52) University of Paris, Imagine Institute, INSERM U1163, 75015 Paris, France; Necker Hospital for Sick Children, AP-HP, 75015 Paris, France. (53) Zahedan University of Medical Sciences, 054 Zahedan, Iran. (54) University of Paris, Imagine Institute, INSERM U1163, 75015 Paris, France; Necker Hospital for Sick Children, AP-HP, 75015 Paris, France. (55) University of Paris, Imagine Institute, INSERM U1163, 75015 Paris, France; Necker Hospital for Sick Children, AP-HP, 75015 Paris, France. (56) Ahvaz Jundishapur University of Medical Sciences, 061 Ahvaz, Iran. (57) McGill University, Montreal, QC H3A 0G1, Canada; McGill Research Centre on Complex Traits, Montreal, QC H3G 0B1, Canada. (58) Pasteur Institute, 75015 Paris, France. (59) University of Paris, Imagine Institute, INSERM U1163, 75015 Paris, France; The Rockefeller University, New York, NY 10065, USA. (60) Papillomavirus National Reference Center, Besanon Hospital, 25030 Besanon, France. (61) Necker Hospital for Sick Children, AP-HP, 75015 Paris, France. (62) University of Paris, Imagine Institute, INSERM U1163, 75015 Paris, France; The Rockefeller University, New York, NY 10065, USA. (63) HHMI, Stanford University Medical School, Stanford, CA 94305, USA. (64) Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia; St. Vincent's Clinical School, UNSW Sydney, Sydney, NSW 2052, Australia. (65) National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA. (66) Sidra Medicine, Doha, Qatar. (67) German Cancer Research Center, 69120 Heidelberg, Germany. (68) McGill University, Montreal, QC H3A 0G1, Canada; McGill Research Centre on Complex Traits, Montreal, QC H3G 0B1, Canada. (69) University of Cambridge, Cambridge CB2 1QP, UK. (70) University of Paris, Imagine Institute, INSERM U1163, 75015 Paris, France; Necker Hospital for Sick Children, AP-HP, 75015 Paris, France. (71) Pennsylvania State University College of Medicine, Hershey, PA 17033, USA. (72) University of Leuven, 3000 Leuven, Belgium. (73) University of Leuven, 3000 Leuven, Belgium; Dr. Shahrooei Lab, Ahvaz, Iran. (74) University of Paris, Imagine Institute, INSERM U1163, 75015 Paris, France; The Rockefeller University, New York, NY 10065, USA; HHMI, New York, NY 10065, USA. Electronic address: casanova@rockefeller.edu.