IL-7 in human health and disease

Abstract

IL-7 plays many essential roles in human health and disease. Congenital deficiencies in IL-7 signaling result in profound immunodeficiency, polymorphisms in IL7Rα modulate susceptibility to autoimmune disease, and acquired somatic activating mutations in IL7Rα contribute to neoplastic transformation in B cell and T cell leukemia. In response to lymphopenia, IL-7 accumulates to supranormal levels, which alters T cell homeostasis by augmenting T cell reactivity toward self and cognate antigens. This physiologic response is now routinely exploited to improve the efficacy of adoptive cell therapies for cancer. Clinical trials of recombinant IL-7 have demonstrated safety and potent immunorestorative effects, and current studies are investigating whether rhIL-7 therapy can improve outcomes in chronic viral infection and in the context of cancer immunotherapies. Building upon the large fund of knowledge regarding the basic biology of IL-7, this review will discuss the many and varied roles of IL-7 in human health and disease.

Figure 1

Figure 1A. BCP-ALL: CRLF2/IL7R axis mutations occurs in 10–15% of cases, is associated with CRLF2 overexpression and a poor prognosis I. Activating JAK2 mutations are found in approximately 8% and are always associated with over expression of CRLF2. II. CRLF2 mutations, most commonly F232C or complex insertions and deletions, encode for an unpaired cysteine in the juxtamembrane domain, leading to homodimerization and CRLF2 activation. III. IL7R S185C mutations found in the juxtamembrane domain (exon 5), are typically associated with overexpression of CRLF2. IV. IL7R insertion and/or deletion mutations in the transmembrane domain (exon 6) encode for an unpaired cysteine, leading to homodimerization and IL7R activation. In BCP-ALL, this mutation is typically associated with overexpression of CRLF2. Figure1B: T cell-ALL: IL7R axis mutations occurs in ~25% of cases, is not associated with CRLF2 expression and does not impact on prognosis. I. Activating JAK1 mutations leading to ligand independent signaling ( ~15% of cases) II. IL7R mutations in exon 6 encoding for an upaired cysteine leads to homodimerization and ligand-, gc- and CRLF2-independent signaling. (~10%)

Figure 1

Figure 1A. BCP-ALL: CRLF2/IL7R axis mutations occurs in 10–15% of cases, is associated with CRLF2 overexpression and a poor prognosis I. Activating JAK2 mutations are found in approximately 8% and are always associated with over expression of CRLF2. II. CRLF2 mutations, most commonly F232C or complex insertions and deletions, encode for an unpaired cysteine in the juxtamembrane domain, leading to homodimerization and CRLF2 activation. III. IL7R S185C mutations found in the juxtamembrane domain (exon 5), are typically associated with overexpression of CRLF2. IV. IL7R insertion and/or deletion mutations in the transmembrane domain (exon 6) encode for an unpaired cysteine, leading to homodimerization and IL7R activation. In BCP-ALL, this mutation is typically associated with overexpression of CRLF2. Figure1B: T cell-ALL: IL7R axis mutations occurs in ~25% of cases, is not associated with CRLF2 expression and does not impact on prognosis. I. Activating JAK1 mutations leading to ligand independent signaling ( ~15% of cases) II. IL7R mutations in exon 6 encoding for an upaired cysteine leads to homodimerization and ligand-, gc- and CRLF2-independent signaling. (~10%)