Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency
Authors: Lévy Romain , Gothe Florian , Momenilandi Mana , Magg Thomas , Materna Marie , Peters Philipp , Raedler Johannes , Philippot Quentin , Rack-Hoch Anita Lena , Langlais David , Bourgey Mathieu , Lanz Anna-Lisa , Ogishi Masato , Rosain Jérémie , Martin Emmanuel , Latour Sylvain , Vladikine Natasha , Distefano Marco , Khan Taushif , Rapaport Franck , Schulz Marian S. , Holzer Ursula , Fasth Anders , Sogkas Georgios , Speckmann Carsten , Troilo Arianna , Bigley Venetia , Roppelt Anna , Dinur-Schejter Yael , Toker Ori , Bronken Martinsen Karen Helene , Sherkat Roya , Somekh Ido , Somech Raz , Shouval Dror S. , Kühl Jörn-Sven , Ip Winnie , McDermott Elizabeth M. , Cliffe Lucy , Ozen Ahmet , Baris Safa , Rangarajan Hemalatha G. , Jouanguy Emmanuelle , Puel Anne , Bustamante Jacinta , Alyanakian Marie-Alexandra , Fusaro Mathieu , Wang Yi , Kong Xiao-Fei , Cobat Aurélie , Boutboul David , Castelle Martin , Aguilar Claire , Hermine Olivier , Cheminant Morgane , Suarez Felipe , Yildiran Alisan , Bousfiha Aziz , Al-Mousa Hamoud , Alsohime Fahad , Cagdas Deniz , Abraham Roshini S. , Knutsen Alan P. , Fevang Borre , Bhattad Sagar , Kiykim Ayca , Erman Baran , Arikoglu Tugba , Unal Ekrem , Kumar Ashish , Geier Christoph B. , Baumann Ulrich , Neven Bénédicte ,   CARMIL2 Consortium, Calas Julie , Feuille Elizabeth , Chan Angela , Yesil Gozde , Nammour Justine , Bandet Élise , Picard Capucine , Benhsaien Ibtihal , Lang Peter , Atschekzei Faranaz , Warnatz Klaus , Hambleton Sophie , Desai Mukesh , Karakoc-Aydiner Elif , Kolukisa Burcu , Al-Muhsen Saleh , Alosaimi Mohammed F. , Cipe Funda , Alazami Anas M. , Hancioglu Gonca , Can Meydan Bilge , Sorte Hanne S. , Stray-Pedersen Asbjørg , Mammayil Geetha , Tökmeci Nazan , Shcherbina Anna , Stepensky Polina , NaserEddin Adeeb , Rouzaud Claire , Hoshino Akihiro , Shamriz Oded , Ledder Oren , Maccari Maria Elena , Castro Carla N. , Grimbacher Bodo , Schmidt Reinhold E. , Collin Matthew , Zakharova Victorya , Rohlfs Meino , Walz Christoph , Abel Laurent , Malissen Bernard , Marr Nico , Klein Christoph , Casanova Jean-Laurent , Hauck Fabian , Béziat Vivien 
Published: December 2022

Patients with inherited CARMIL2 or CD28 deficiency have defective T cell CD28 signaling, but their immunological and clinical phenotypes remain largely unknown. We show that only one of three CARMIL2 isoforms is produced and functional across leukocyte subsets. Tested mutant CARMIL2 alleles from 89 patients and 52 families impair canonical NF-κB but not AP-1 and NFAT activation in T cells stimulated via CD28. Like CD28-deficient patients, CARMIL2-deficient patients display recalcitrant warts and low blood counts of CD4+ and CD8+ memory T cells and CD4+ TREGs. Unlike CD28-deficient patients, they have low counts of NK cells and memory B cells, and their antibody responses are weak. CARMIL2 deficiency is fully penetrant by the age of 10 yr and is characterized by numerous infections, EBV+ smooth muscle tumors, and mucocutaneous inflammation, including inflammatory bowel disease. Patients with somatic reversions of a mutant allele in CD4+ T cells have milder phenotypes. Our study suggests that CARMIL2 governs immunological pathways beyond CD28.