The human IL-7 receptor gene: Deletions, polymorphisms and mutations

doi:10.1016/j.smim.2012.02.007

Seminars in Immunology

Volume 24, Issue 3, June 2012, Pages 225-230

https://doi.org/10.1016/j.smim.2012.02.007 Get rights and content

Abstract

Most T cell subsets depend on IL-7 for survival. IL-7 binds to IL-7Rα and γc, initiating the signaling cascade. Deletion of IL-7Ra in humans has, for some time, been known to cause severe combined immunodeficiency. More recently, polymorphisms in IL-7R have been shown be a risk factor for a number of diseases that are autoimmune or involve excess immune and inflammatory responses including multiple sclerosis, type 1 diabetes, rheumatoid arthritis, primary biliary cirrhosis, inflammatory bowel disease, atopic dermatitis, inhalation allergy, sarcoidosis and graft-versus host disease. The polymorphism that affects risk to most of these immunopathologies is T244I at the border of the extracellular domain and the transmembrane region. The same region has recently been shown to harbor gain-of-function mutations in acute lymphoblastic leukemia. These studies have suggested new therapies that target the IL-7 pathway.

Highlights

► Polymorphisms in IL-7R have recently been linked to a number of immunopathologies. ► Immunopathologies include multiple sclerosis, type 1 diabetes and rheumatoid arthritis. ► They also include inflammatory bowel disease, inhalation allergy and others. ► We propose a new mechanism for the IL-7R polymorphism effect in immunopathology. ► Gain-of-function mutations in IL-7R occur in acute lymphoblastic leukemia.

Introduction

Interleukin-7 (IL-7) was initially discovered as a factor promoting B cell development in mice (reviewed in [1], [2]) and more recently in human B cell development [3]. IL-7 was later shown to be essential for T cell development in the thymus and for survival and proliferation of memory and naive T cells (reviewed in [4]) and T helper type 17 (Th17) cells [5]. IL-7 function is mediated by the IL-7 receptor, a membrane receptor composed of the specific IL-7Rα chain and the γc chain shared by receptors for other cytokines (IL-2, -4, -9, -15 and -21). In this review, we will use the term “IL-7R” to refer to the gene encoding IL-7Rα. The phenotypes of both IL-7 and IL-7R knockout mice are dramatically lymphopenic [6], [7] and defects in IL7-R cause severe immunodeficiency in humans [8] as will be discussed. TSLP is an additional ligand for IL-7R [9], and as we discuss the human impact of IL-7R variants in this review, it should be kept in mind that both the IL-7 and TSLP pathways could be involved.

Section snippets

Immunodeficiency

Severe combined immunodeficiency (SCID) is a heterogeneous group of genetic disorders caused by mutations in a number of genes involved in the development of lymphocytes. X-linked SCID is the most frequent and is caused by mutations in the gene for the γc chain [10]. The phenotype of γc-deficient SCID is characterized by absence of T and NK cells and a normal number of B lymphocytes [11], [12]. Although γc is shared by other cytokine receptors, the T cell deficiency is largely attributable to

Autoimmunity

The IL-7 pathway is essential to immune system development and maintenance in physiological conditions. However, genetic variations in IL-7R are implicated in several severe autoimmune disorders (summarized in Table 1). There is a common genetic basis for several of these as will be discussed.

Excess immune and inflammatory responses

IL-7 is a homeostatic cytokine controlling survival and proliferation of naïve and memory T cells. As suggested in the preceding sections, excess signaling from the IL-7R is implicated in autoimmune diseases, and as we will discuss, other pathologies attributed to excess immune and inflammatory responses.

Acute lymphoblastic leukemia

The IL-7 pathway has long been suspected to play a role in lymphoid cancers because of its effects of inducing survival and proliferation of normal lymphocytes. IL-7R was detected on both T-cell acute lymphoblastic leukemia (T-ALL) [85], [86], [87], [88], [89] and B-cell chronic lymphocytic leukemia (B-CLL) [90], [91] and in vitro, IL-7 induced proliferation of T- and B-ALL cells [85], [88], [92], [93]. Although most cells from ALL patients proliferated without differentiation [86], [93], [94],

Conclusions

Deficiency of the IL-7 receptor pathway has been known for some time to cause the dramatic phenotype of SCID. More recent studies show the effects of more subtle perturbations in IL-7R. Given the potent effects of the IL-7 pathway in lymphocytes, it is perhaps not surprising that genetic variations in IL-7R could contribute to immunopathologic diseases. We have discussed the effects of polymorphisms in autoimmunity and in excess immune/inflammatory disorders, and of mutations driving leukemia.

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A spectrum of autoimmune and immune-excess disorders has implicated the IL-7 receptor pathway based on animal models, GWAS, and other human studies. These include multiple sclerosis, type 1 diabetes, atopic dermatitis, IBD and asthma (reviewed in [375]). T-cell acute lymphoblastic leukemia (T-ALL) is driven by the IL-7 receptor pathway (reviewed in [408]).
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Interleukin 7 (IL7) human IL7: gene ID: 3574 on ch 8; murine Il7 gene ID: 16,196 on ch 3.
Precursor contains a signal sequence, mature human IL-7 peptide 152aa, predicted 17.4kd peptide, glycosylated resulting in 25kd. Crystal structure: http://www.rcsb.org/structure/3DI2.
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Major signals through JAK1, JAK3 to STAT5 and through non-canonical STAT3, STAT1, PI3K/AKT and MEK/ERK pathways.
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Deficiencies in the IL-7 pathway in humans and mice result in severe combined immunodeficiency due to lymphopenia. Excessive signaling of the pathway in mice drives autoimmune diseases and in humans is associated with autoimmune syndromes including multiple sclerosis, type 1 diabetes, rheumatoid arthritis, sarcoidosis, atopic dermatitis and asthma. Mutations in the IL-7 receptor pathway drive acute lymphoblastic leukemia.
IL-7 has been evaluated in patients with cancer and shown to expand lymphocytes. It accelerated lymphocyte recovery after hematopoietic stem cell transfer, and increased lymphocyte counts in AIDS patients and sepsis patients. Monoclonal antibodies blocking the IL-7 receptor are being evaluated in autoimmune diseases. Cytotoxic monoclonals are being evaluated in acute lymphoblastic leukemia. Drugs blocking the signal transduction pathway are being tested in autoimmunity and acute lymphoblastic leukemia.
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Published by Elsevier Ltd.

ReviewThe human IL-7 receptor gene: Deletions, polymorphisms and mutations

Abstract

Highlights

Introduction

Section snippets

Immunodeficiency

Autoimmunity

Excess immune and inflammatory responses

Acute lymphoblastic leukemia

Conclusions

Cytokine Growth Factor Rev

Cell

Genet Med

Blood

Ann Allergy Asthma Immunol

J Allergy Clin Immunol

Clin Immunol

J Allergy Clin Immunol

J Pediatr

Cytokine

J Neuroimmunol

Immunity

Genes Immun

J Neuroimmunol

J Autoimmun

J Dermatol Sci

J Neuroimmunol

Gastroenterology

J Allergy Clin Immunol

Clin Immunol Immunopathol

J Allergy Clin Immunol

Blood

Blood

Blood

Blood

Blood

Interleukin-7 receptor expression: intelligent design

Nat Rev Immunol

IL-7 dependence in human B lymphopoiesis increases during progression of ontogeny from cord blood to bone marrow

J Immunol

The many faces of IL-7: from lymphopoiesis to peripheral T cell maintenance

J Immunol

Crucial role of interleukin-7 in T helper type 17 survival and expansion in autoimmune disease

Nat Med

Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice

J Exp Med

Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine

J Exp Med

Defective IL7R expression in T(−)B(+)NK(+) severe combined immunodeficiency

Nat Genet

Thymic stromal lymphopoietin: a cytokine that promotes the development of IgM+ B cells in vitro and signals via a novel mechanism

J Immunol

Interleukin-7 receptor alpha (IL-7Ralpha) deficiency: cellular and molecular bases. Analysis of clinical, immunological, and molecular features in 16 novel patients

Immunol Rev

Characterization of a novel nonsense mutation in the interleukin-7 receptor alpha gene in a Korean patient with severe combined immunodeficiency

Int J Hematol

Severe combined immunodeficiency: a national surveillance study

Pediatr Allergy Immunol

Delayed onset of (severe) combined immunodeficiency (S)CID (T-B+NK+): complete IL-7 receptor deficiency in a 22 months old girl

Klin Padiatr

IL-7Ralpha confers susceptibility to experimental autoimmune encephalomyelitis

Genes Immun

Identification of 11 novel and common single nucleotide polymorphisms in the interleukin-7 receptor-alpha gene and their associations with multiple sclerosis

Eur J Hum Genet

Gene expression and genotyping studies implicate the interleukin 7 receptor in the pathogenesis of primary progressive multiple sclerosis

J Mol Med (Berl)

Risk alleles for multiple sclerosis identified by a genomewide study

N Engl J Med

Interleukin 7 receptor alpha chain (IL7R) shows allelic and functional association with multiple sclerosis

Nat Genet

IL2RA and IL7RA genes confer susceptibility for multiple sclerosis in two independent European populations

Genes Immun

The T244I variant of the interleukin-7 receptor-alpha gene and multiple sclerosis

Tissue Antigens

Risk alleles for multiple sclerosis in multiplex families

Neurology

Haplotype 4 of the multiple sclerosis-associated interleukin-7 receptor alpha gene influences the frequency of recent thymic emigrants

Genes Immun

Variation in SNPs of the IL7Ra gene is associated with multiple sclerosis in the Iranian population

Immunol Invest

Review
The human IL-7 receptor gene: Deletions, polymorphisms and mutations