Cytotoxic T-lymphocyte-associated protein 4 haploinsufficiency-associated inflammation can occur independently of T-cell hyperproliferation

Carole Le Coz, Brian Edward Nolan, Melissa Trofa, Alicia M. Kamsheh, Mustafa K. Khokha, Saquib A. Lakhani, Antonio Novelli, Elaine H. Zackai, Kathleen E. Sullivan, Silvana Briuglia, Tricia R. Bhatti, Neil Romberg*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


Located contiguously on the long arm of the second chromosome are gene paralogs encoding the immunoglobulin-family co-activation receptors CD28 and cytotoxic T-lymphocyte-associated protein 4 (CTLA4). CD28 and CTLA4 share the same B7 ligands yet each provides opposing proliferative signals to T cells. Herein, we describe for the first time two unrelated subjects with coexisting CD28 and CTLA4 haploinsufficiency due to heterozygous microdeletions of chromosome 2q. Although their clinical phenotype, multi-organ inflammatory disease, is superficially similar to that of CTLA4 haploinsufficient autoimmune lymphoproliferative syndrome type V (ALPS5) patients, we demonstrate our subjects' underlying immunopathology to be distinct. Unlike ALPS5 T cells which hyperproliferate to T-cell receptor-mediated activation and infiltrate organs, T cells from our subjects are hypoproliferative and do not. Instead of T cell infiltrates, biopsies of affected subject tissues demonstrated infiltrates of lineage negative lymphoid cells. This histologic feature correlated with significant increases in circulating type 3 innate lymphoid cells (ILC3s) and ILC3 cytokines, interleukin 22, and interleukin-17A. CTLA4-Ig monotherapy, which we trialed in one subject, was remarkably effective in controlling inflammatory diseases, normalizing ILC3 frequencies, and reducing ILC3 cytokine concentrations.

Original languageEnglish (US)
Article number1715
JournalFrontiers in immunology
Issue numberJUL
StatePublished - Jul 24 2018


  • CD28
  • Cytotoxic T-lymphocyte-associated protein 4
  • Inflammation
  • Regulatory T cell
  • Type 3 innate lymphoid cell

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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