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Updated: Aug 1, 2026
Detection and Isolation of Viable Mouse IL-17-Secreting T Cells
Published on: December 18, 2008
CD4 ligand IL-16 inhibits the mixed lymphocyte reaction
A C Theodore1, D M Center, J Nicoll
1The Pulmonary Center, Boston University School of Medicine, MA 02118, USA.
Insights
Interleukin-16 (IL-16) suppresses T cell proliferation by interfering with IL-2 receptor signaling, distinct from other CD4 ligands. This finding clarifies CD4
Area of Science:
- Immunology
- Cellular Biology
- Molecular Signaling
Background:
- CD4 receptor interaction with MHC class II antigens promotes T cell activation.
- Binding of CD4 to alternative ligands like HIV-1 gp120 or anti-CD4 antibodies inhibits T cell receptor signaling, inducing unresponsiveness.
Purpose of the Study:
- To investigate whether the natural CD4 ligand, interleukin-16 (IL-16), also induces T cell unresponsiveness.
- To elucidate the mechanism by which IL-16 affects T cell proliferation and signaling.
Main Methods:
- Mixed lymphocyte reactions were used to assess T cell proliferation.
- Recombinant IL-16 (rIL-16) was added at varying concentrations to evaluate its suppressive effects.
- Flow cytometry was used to assess CD4 and IL-2 receptor expression.
- T cell viability and basal proliferation were measured.
Main Results:
- rIL-16 suppressed T cell proliferation in a dose-dependent manner.
- The suppressive effect was observed between days 5 and 9 of the mixed lymphocyte reaction.
- rIL-16 did not alter CD4 expression, basal proliferation, or viability.
- Neutralizing anti-rIL-16 monoclonal antibodies or soluble CD4 blocked the suppressive effect.
- IL-2 receptor expression remained unaffected, and exogenous IL-2 did not restore proliferation, suggesting a disruption in IL-2 receptor signaling.
Conclusions:
- IL-16 acts as an inhibitory CD4 ligand, suppressing T cell proliferation.
- The mechanism of IL-16-induced unresponsiveness involves an interruption in IL-2 receptor signaling, distinct from other CD4 ligands.
- These findings provide insights into the dual role of CD4 in signal transduction and the regulatory function of IL-16 in immune responses.
Abstract:
CD4 participation in TCR/CD3-associated activation through interaction with the MHC class II Ags results in formation of a CD4-TCR/CD3 complex capable of maximal signal transduction. When CD4 binds to alternative ligands such as HIV-1 gp120 or anti-CD4 Abs, Ag stimulation of TCR/CD3 is markedly inhibited, and an unresponsive state develops. To determine if the natural CD4 ligand interleukin-16 also induces unresponsiveness, we tested the effects of rIL-16 on T cell proliferation in mixed lymphocyte reactions. rIL-16 suppressed T cell proliferation in a dose-dependent manner at concentrations of 10(-11) to 10(-7) M. Inhibition of proliferation was present on days 5 to 9 of the mixed lymphocyte reaction. rIL-16 did not modulate membrane CD4, significantly change basal [3H]thymidine incorporation in resting T lymphocytes, or alter viability. The suppressive effect was specifically blocked by preincubation with neutralizing anti-rIL-16 mAb or with recombinant soluble CD4. While the expression of IL-2R on responder cells was unaffected by rIL-16, the addition of exogenous rIL-2 did not restore T cell responsiveness. The unresponsiveness induced by rIL-16 is distinct from that of other CD4 ligands in that CD4 and IL-2R expression are unaffected. The failure of rIL-2 to restore proliferation suggests that the decrease in T cell responsiveness induced by rIL-16 may result from an interruption in the IL-2R-signaling mechanism. These results may help explain how CD4 delivers both activating and inhibitory signals and provides a rationale for the role of IL-16 in the regulation of immune responses.
