Interleukin‐4 downregulates CD127 expression and activity on human thymocytes and mature CD8⁺ T cells

Abstract

Signaling via the IL-7 receptor complex (IL-7Ra/CD127 and IL-2Rc/CD132) is required for T-cell development and survival. Decreased CD127 expression has been associated with persistent viral infections (e.g. HIV, HCV) and cancer. Many IL-2Rc-sharing (c C ) cytokines decrease CD127 expression on CD4 1 and CD8 1 T cells in mice (IL-2, IL-4, IL-7, IL-15) and in humans (IL-2, IL-7), suggesting a common function. IL-4 is of particular interest as it is upregulated in HIV infection and in thyroid and colon cancers. The role of IL-4 in regulating CD127 expression and IL-7 activity in human thymocytes and mature CD8 1 T cells is unknown and was therefore investigated. IL-4 decreased CD127 expression on all thymocyte subsets tested and only on naïve (CD45RA 1 ) CD8 1 T cells, without altering membrane-bound CD127 mRNA expression. Pre-treatment of thymocytes or CD8 1 T cells with IL-4 inhibited IL-7-mediated phosphorylation of STAT5 and decreased proliferation of CD8 1 T cells. By downregulating CD127 expression and signaling on developing thymocytes and CD8 1 T cells, IL-4 is a potential contributor to impaired CD8 1 T-cell function in some anti-viral and anti-tumor responses. These findings are of particular consequence to diseases such as HIV, HCV, RSV, measles and cancer, in which CD127 expression is decreased, IL-7 activity is impaired and IL-4 concentrations are elevated.

In Vitro HIV Type 1 Infection Indirectly Alters CD127 Expression on CD8+ T Cells

“…IL-7 and IL-4) has been investigated in vitro, and both IL-7 and IL-4 have been shown to decrease CD127 expression on CD8 + T cells. 8,9,13 In the present study, the addition of anti-IL-7 or anti-IL-4 antibodies did not reverse the downregulation of CD127 observed on CD8 + T cells with HIV-infected PBMC cultures, nor was the concentrations of IL-7 or IL-4 in culture supernatants found to be elevated (data not shown).…”

“…12,14 Similarly, the transient nature of CD127 downregulation has also been observed when CD8 + T cells are incubated with IL-7 or IL-4. 8,9,13 The observation that HIV-tat, to the exclusion of other HIV proteins, decreases CD127 on CD8…”

“…Furthermore, the concentrations of IL-7 and IL-4 required to decrease CD127 expression in vitro exceed levels found in plasma. 9,13 Similarly, the concentration of other cytokines in the IL-2R c-chain sharing family (IL-2, -9, -15, -21), some of which have been shown to decrease CD127 expression, 15 may be too low in vitro to alter CD127 expression.…”

Complexed soluble IL-7 receptor α and IL-7 increase IL-7-mediated proliferation and viability of CD8+ T-cells in vitro

“…Signaling via IL-7 receptor (IL-7R) complex (includes the membrane IL-7Ra chain (mIL-7Ra) and the common c-chain (c C )), IL-7 has potent effects on T-cell progenitors and its importance in T-cell homeostasis is well established. The delivery of IL-7 signals is dependent in part on cytokine-and T-cell activation-regulated mIL-7Ra expression, and soluble IL-7Ra (sIL-7Ra) release [6,7]. The mechanisms of production and the biological role of endogenous sIL-7Ra in IL-7 activity remain poorly understood and are the subject of ongoing study.…”

Infectious Bursal Disease Virus Influences the Transcription of Chicken γc and γc Family Cytokines during Infection

“…IL-2 promotes proliferation of B cells, contributes to the development of regulatory T cells and regulates the proliferation and apoptosis of activated T cells [8]. IL-4 is required for T helper 2 cell developments and is a potential contributor to impaired CD8 + T-cell function in some anti-viral responses [9]. IL-7 has a central role in T-cell development [10], [11], [12], increased intrathymic IL-7 signaling significantly enhances the maintenance of immature thymocytes.…”