Clonal haematopoiesis and dysregulation of the immune system

Abstract

Age-related diseases are frequently linked to pathological immune dysfunction, including excessive inflammation, autoreactivity and immunodeficiency. Recent analyses of human genetic data have revealed that somatic mutations and mosaic chromosomal alterations in blood cells - a condition known as clonal haematopoiesis (CH) - are associated with ageing and pathological immune dysfunction. Indeed, large-scale epidemiological studies and experimental mouse models have demonstrated that CH can promote cardiovascular disease, chronic obstructive pulmonary disease, chronic liver disease, osteoporosis and gout. The genes most frequently mutated in CH, the epigenetic regulators TET2 and DNMT3A, implicate increased chemokine expression and inflammasome hyperactivation in myeloid cells as a possible mechanistic connection between CH and age-related diseases. In addition, TET2 and DNMT3A mutations in lymphoid cells have been shown to drive methylation-dependent alterations in differentiation and function. Here we review the observational and mechanistic studies describing the connection between CH and pathological immune dysfunction, the effects of CH-associated genetic alterations on the function of myeloid and lymphoid cells, and the clinical and therapeutic implications of CH as a target for immunomodulation.

Figure 1 |. Features of clonal haematopoiesis.

Analysis of human genetic data has led to the discovery of somatic mutations in peripheral blood cells. These mutations comprise non-synonymous variants in genes frequently altered in myeloid malignancies (for example, DNMT3A, TET2 and ASXL1) as well as mosaic chromosomal abnormalities. These genetic alterations occur in a clonal subpopulation of blood cells and are detected more frequently in older individuals. Mutations in different genes tend to follow unique trajectories of clonal expansion over time^–,, implying distinct mechanisms of positive selection for different mutations. Clonal haematopoiesis has also been linked to several clinical phenotypes, including incident myeloid and lymphoid neoplasms, non-malignant diagnoses (such as atherosclerosis) and overall mortality. Images courtesy of the Department of Pathology at the Brigham and Women’s Hospital, Boston, USA.

Figure 2 |. Functional effects of clonal haematopoiesis-associated mutations in myeloid cells.

Evidence from mouse models and human observational studies indicate that mutations in genes associated with clonal haematopoiesis can affect the differentiation and function of mature myeloid cells. a | In monocytes and macrophages, the effects of genetic alterations in Tet2, Dnmt3a and Jak2 have been studied most extensively, revealing increased chemokine expression, hyperactivation of the inflammasome and increased IL-1β as common features^,–,,,. In response to viral infection and Toll-like receptor (TLR) stimuli, Dnmt3a mutant macrophages produce less type I interferons (IFNs), correlating with reduced survival of virally-infected mice with Dnmt3a-deficient myeloid cells. Elevated myeloid production of IL-20 in the setting of Dnmt3a deficiency is associated with increased in osteoclastogenesis and osteoporosis, whereas Asxl1 loss in myeloid cells correlates with increased NFATc1 activity and osteoclast differentiation. b | In neutrophils, JAK2 V617F is associated with neutrophil extracellular trap (NET) formation and thrombosis in both mouse and human studies^,. Mouse and zebrafish models have also demonstrated a role for Tet2 and Tet3 in neutrophil mobility, phagocytosis and granule formation. c | In mast cells, Tet2 loss has contrasting effects – either suppressing mast cell differentiation and stimulating mast cell proliferation via C/EBP transcription factors, or suppressing mast cell expansion in response to Schistosoma infection. Mast cells lacking Dnmt3a demonstrated higher cytokine production upon acute stimulation, whereas Asxl1 truncating mutations promote mast cell differentiation in a multipotent haematopoietic precursor cell line. d | In dendritic cells, Tet2 loss resulted in higher IL-6 levels and reduced type I IFN production in response to challenge with herpes simplex virus or vesicular stomatitis virus (VSV)^,. Similarly, Dnmt3a loss reduces type I IFN production in response to VSV.

Figure 3 |. Impact of TET2 and DNMT3A loss in lymphocytes.

a | In antigen-stimulated mouse CD8⁺ T cells and human chimeric antigen receptor (CAR) T cells, deficiency in DNMT3A or TET2 is associated with normal primary immune responses but enhanced secondary responses with increased memory precursor and central memory T cell differentiation^–,,. These phenotypic changes correlate with increased expression of the master transcription factors TCF1 (encoded by Tcf7) or EOMES in absence of DNMT3A or TET2, respectively^–,,. While TET2 deficiency does not result in significant methylation changes at the Eomes locus, DNMT3A deficiency leads to a reduction in Tcf7 promoter methylation, consistent with DNMT3A localization to the Tcf7 promoter in DNMT3A wild-type T cells. b | In mouse CD4⁺ T cells and innate lymphoid cell (ILC) subsets, TET2 is recruited to the Il17a enhancer CNS2 via RORγt, leading to increased enhancer and promoter hydroxymethylation and increased Il17a expression. In this context, IL-17A production by T helper 17 (T_H17) cells, group 3 innate lymphoid cells (ILC3s) and inflammatory group 2 innate lymphoid cells (iILC2s) is significantly reduced in the setting of TET2 deficiency^,. Similarly, DNMT3A localization to the Ifng promoter in T helper 2 (T_H2) cells, T helper 17 (T_H17) cells and regulatory T (T_reg) cells generated in vitro is associated with increased methylation and reduced Ifng expression; reduced Ifng methylation in DNMT3A-deficient T_H2, T_H17 and T_reg cells leads to aberrant IFNγ production by all three subsets upon restimulation with the T_H1 cytokine IL-12. c | In B cells, TET2 deficiency during primary immunization is associated with accumulation of germinal centre B cells, reduced expression of the plasma cell-defining transcription factor PRDM1, impaired plasma cell differentiation and decreased production of antigen-specific antibodies upon secondary immunization. Reduced PRDM1 expression in the absence of TET2 correlates with hypermethylation within Prdm1 intron 2, which contains a locus that undergoes progressive demethylation during plasma cell differentiation, as well as decreased hydroxymethylation of an intergenic enhancer.