Loss-of-function mutations have provided crucial insights into the immunoregulatory actions of Fo... more Loss-of-function mutations have provided crucial insights into the immunoregulatory actions of Foxp3 + regulatory T cells (Tregs). By contrast, we know very little about the consequences of defects that amplify aspects of Treg function or differentiation. We report that mice heterozygous for an Ikbkb gain-of-function (GoF) mutation develop psoriasis. Doubling the gene dose (IkbkbGoF/GoF) results in dactylitis, spondylitis, and characteristic nail changes, which are features of psoriatic arthritis. IkbkbGoF mice exhibit a selective expansion of Foxp3 + CD25 + Tregs of which a subset express IL-17. These modified Tregs were enriched in both inflamed tissues and spleen, and their transfer was sufficient to induce disease without conventional T cells. Single-cell transcriptional and phenotyping analyses of isolated Tregs revealed expansion of non-lymphoid tissue (tissue-resident) Tregs expressing Th17-related genes, Helios, tissue-resident markers including CD103 and CD69, and a promine...
As chronic antigenic stimulation from infection and autoimmunity are features of primary antibody... more As chronic antigenic stimulation from infection and autoimmunity are features of primary antibody deficiency (PAD), analysis of affected patients could yield insights into T cell differentiation, and explain how environmental exposures modify clinical phenotypes conferred by single gene defects. CD57 marks dysfunctional T cells that have differentiated after antigenic stimulation. Indeed, while CD57+ CD4+ T cells are normally rare in the circulation, we found that they are increased in patients with PAD, and markedly by CTLA4 haploinsufficiency or blockade. We performed single-cell RNA-seq analysis of matched CD57+ CD4+ T cells from blood and tonsil. Circulating CD57+ CD4+ T cells (CD4cyt) exhibit a cytotoxic transcriptome similar to CD8+ effectors, can kill B cells, and inhibit B cell responses. CTLA4 restrains the formation of CD4cyt. While CD57 also marks an abundant subset of follicular helper T cells, which is consistent with their antigen-driven differentiation, this subset has a precursor of exhaustion transcriptomic signature marked by TCF7, TOX, ID3, and constitutive expression of CTLA4, and are robust to becoming cytotoxic even after CTLA4 inhibition. Thus, CD57+ CD4+ T cell phenotypes of cytotoxicity and exhaustion are compartmentalized between blood and germinal centres. CTLA4 is a key modifier of CD4+ T cell cytotoxicity, and the pathological CD4cyt phenotype is accentuated in CTLA4 deficiency by the environmental stimulus of infection.
As chronic antigenic stimulation from infection and autoimmunity is a feature of primary antibody... more As chronic antigenic stimulation from infection and autoimmunity is a feature of primary antibody deficiency (PAD), analysis of affected patients could yield insights into T-cell differentiation and explain how environmental exposures modify clinical phenotypes conferred by single-gene defects. CD57 marks dysfunctional T cells that have differentiated after antigenic stimulation. Indeed, while circulating CD57+ CD4+ T cells are normally rare, we found that they are increased in patients with PAD and markedly increased with CTLA4 haploinsufficiency or blockade. We performed single-cell RNA-seq analysis of matched CD57+ CD4+ T cells from blood and tonsil samples. Circulating CD57+ CD4+ T cells (CD4cyt) exhibited a cytotoxic transcriptome similar to that of CD8+ effector cells, could kill B cells, and inhibited B-cell responses. CTLA4 restrained the formation of CD4cyt. While CD57 also marked an abundant subset of follicular helper T cells, which is consistent with their antigen-driven...
As chronic antigenic stimulation from infection and autoimmunity are features of primary antibody... more As chronic antigenic stimulation from infection and autoimmunity are features of primary antibody deficiency (PAD), analysis of affected patients could yield insights into T cell differentiation, and explain how environmental exposures modify clinical phenotypes conferred by single gene defects. CD57 marks dysfunctional T cells that have differentiated after antigenic stimulation. Indeed, while CD57+ CD4+ T cells are normally rare in the circulation, we found that they are increased in patients with PAD, and markedly by CTLA4 haploinsufficiency or blockade. We performed single-cell RNA-seq analysis of matched CD57+ CD4+ T cells from blood and tonsil. Circulating CD57+ CD4+ T cells (CD4cyt) exhibit a cytotoxic transcriptome similar to CD8+ effectors, can kill B cells, and inhibit B cell responses. CTLA4 restrains the formation of CD4cyt. While CD57 also marks an abundant subset of follicular helper T cells, which is consistent with their antigen-driven differentiation, this subset ha...
The Journal of experimental medicine, Jan 18, 2018
Genetic mutations account for many devastating early onset immune deficiencies. In contrast, less... more Genetic mutations account for many devastating early onset immune deficiencies. In contrast, less severe and later onset immune diseases, including in patients with no prior family history, remain poorly understood. Whole exome sequencing in two cohorts of such patients identified a novel heterozygous de novo missense mutation (c.607G>A) in two separate kindreds in whom probands presented with immune dysregulation, combined T and B cell deficiency, inflammation, and epithelial defects. encodes IKK2, which activates NF-κB signaling. IKK2 results in enhanced NF-κB signaling, as well as T and B cell functional defects. IKK2 is a highly conserved residue, and to prove causation, we generated an accurate mouse model by introducing the precise orthologous codon change in using CRISPR/Cas9. Mice and humans carrying this missense mutation exhibit remarkably similar cellular and biochemical phenotypes. Accurate mouse models engineered by CRISPR/Cas9 can help characterize novel syndromes a...
Loss-of-function mutations have provided crucial insights into the immunoregulatory actions of Fo... more Loss-of-function mutations have provided crucial insights into the immunoregulatory actions of Foxp3 + regulatory T cells (Tregs). By contrast, we know very little about the consequences of defects that amplify aspects of Treg function or differentiation. We report that mice heterozygous for an Ikbkb gain-of-function (GoF) mutation develop psoriasis. Doubling the gene dose (IkbkbGoF/GoF) results in dactylitis, spondylitis, and characteristic nail changes, which are features of psoriatic arthritis. IkbkbGoF mice exhibit a selective expansion of Foxp3 + CD25 + Tregs of which a subset express IL-17. These modified Tregs were enriched in both inflamed tissues and spleen, and their transfer was sufficient to induce disease without conventional T cells. Single-cell transcriptional and phenotyping analyses of isolated Tregs revealed expansion of non-lymphoid tissue (tissue-resident) Tregs expressing Th17-related genes, Helios, tissue-resident markers including CD103 and CD69, and a promine...
As chronic antigenic stimulation from infection and autoimmunity are features of primary antibody... more As chronic antigenic stimulation from infection and autoimmunity are features of primary antibody deficiency (PAD), analysis of affected patients could yield insights into T cell differentiation, and explain how environmental exposures modify clinical phenotypes conferred by single gene defects. CD57 marks dysfunctional T cells that have differentiated after antigenic stimulation. Indeed, while CD57+ CD4+ T cells are normally rare in the circulation, we found that they are increased in patients with PAD, and markedly by CTLA4 haploinsufficiency or blockade. We performed single-cell RNA-seq analysis of matched CD57+ CD4+ T cells from blood and tonsil. Circulating CD57+ CD4+ T cells (CD4cyt) exhibit a cytotoxic transcriptome similar to CD8+ effectors, can kill B cells, and inhibit B cell responses. CTLA4 restrains the formation of CD4cyt. While CD57 also marks an abundant subset of follicular helper T cells, which is consistent with their antigen-driven differentiation, this subset has a precursor of exhaustion transcriptomic signature marked by TCF7, TOX, ID3, and constitutive expression of CTLA4, and are robust to becoming cytotoxic even after CTLA4 inhibition. Thus, CD57+ CD4+ T cell phenotypes of cytotoxicity and exhaustion are compartmentalized between blood and germinal centres. CTLA4 is a key modifier of CD4+ T cell cytotoxicity, and the pathological CD4cyt phenotype is accentuated in CTLA4 deficiency by the environmental stimulus of infection.
As chronic antigenic stimulation from infection and autoimmunity is a feature of primary antibody... more As chronic antigenic stimulation from infection and autoimmunity is a feature of primary antibody deficiency (PAD), analysis of affected patients could yield insights into T-cell differentiation and explain how environmental exposures modify clinical phenotypes conferred by single-gene defects. CD57 marks dysfunctional T cells that have differentiated after antigenic stimulation. Indeed, while circulating CD57+ CD4+ T cells are normally rare, we found that they are increased in patients with PAD and markedly increased with CTLA4 haploinsufficiency or blockade. We performed single-cell RNA-seq analysis of matched CD57+ CD4+ T cells from blood and tonsil samples. Circulating CD57+ CD4+ T cells (CD4cyt) exhibited a cytotoxic transcriptome similar to that of CD8+ effector cells, could kill B cells, and inhibited B-cell responses. CTLA4 restrained the formation of CD4cyt. While CD57 also marked an abundant subset of follicular helper T cells, which is consistent with their antigen-driven...
As chronic antigenic stimulation from infection and autoimmunity are features of primary antibody... more As chronic antigenic stimulation from infection and autoimmunity are features of primary antibody deficiency (PAD), analysis of affected patients could yield insights into T cell differentiation, and explain how environmental exposures modify clinical phenotypes conferred by single gene defects. CD57 marks dysfunctional T cells that have differentiated after antigenic stimulation. Indeed, while CD57+ CD4+ T cells are normally rare in the circulation, we found that they are increased in patients with PAD, and markedly by CTLA4 haploinsufficiency or blockade. We performed single-cell RNA-seq analysis of matched CD57+ CD4+ T cells from blood and tonsil. Circulating CD57+ CD4+ T cells (CD4cyt) exhibit a cytotoxic transcriptome similar to CD8+ effectors, can kill B cells, and inhibit B cell responses. CTLA4 restrains the formation of CD4cyt. While CD57 also marks an abundant subset of follicular helper T cells, which is consistent with their antigen-driven differentiation, this subset ha...
The Journal of experimental medicine, Jan 18, 2018
Genetic mutations account for many devastating early onset immune deficiencies. In contrast, less... more Genetic mutations account for many devastating early onset immune deficiencies. In contrast, less severe and later onset immune diseases, including in patients with no prior family history, remain poorly understood. Whole exome sequencing in two cohorts of such patients identified a novel heterozygous de novo missense mutation (c.607G>A) in two separate kindreds in whom probands presented with immune dysregulation, combined T and B cell deficiency, inflammation, and epithelial defects. encodes IKK2, which activates NF-κB signaling. IKK2 results in enhanced NF-κB signaling, as well as T and B cell functional defects. IKK2 is a highly conserved residue, and to prove causation, we generated an accurate mouse model by introducing the precise orthologous codon change in using CRISPR/Cas9. Mice and humans carrying this missense mutation exhibit remarkably similar cellular and biochemical phenotypes. Accurate mouse models engineered by CRISPR/Cas9 can help characterize novel syndromes a...
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