Evidence for CD4-enchanced signaling through the chemokine receptor CCR5.
The chemokine receptor CCR5 is constitutively associated with the T cell co-receptor CD4 in plasma cell membranes, but the physiological role of this interaction has not been elucidated. Here we show that detergent-solubilized, purified CCR5 can directly associate with purified soluble fragments of the extracellular portion of CD4. We further demonstrate that the physical association of CCR5 and CD4 in membrane vesicles results in the formation of a receptor complex that exhibits macrophage inflammatory protein 1beta (MIP-1beta) binding properties that are distinct from CCR5. The affinity of the CD4-CCR5 complex for MIP-1beta was 3.5-fold lower than for CCR5, but the interaction of CD4 and CCR5 resulted in a receptor complex that exhibited enhanced G-protein signaling as compared with CCR5 alone. MIP-1beta-induced G-protein activation was further increased by simultaneous stimulation of CD4 with its natural agonist, interleukin-16. Thus, the physical association of CD4 and CCR5 results in receptor cross-talk with allosteric CD4-dependent regulation of the binding and signaling properties of CCR5. Although the precise physiological role of the CD4 effects on CCR5-mediated signaling remains unknown, one can speculate that the cross-talk is a component of mechanisms involved in the fine tuning of immune system cell responses.
Staudinger
Robert
R
Veterans Affairs New York Harbor Healthcare System, New York, New York 10016, USA. robert.staudinger@med.nyu.edu
Phogat
Sanjay K
SK
Xiao
Xiaodong
X
Wang
Xiahong
X
Dimitrov
Dimiter S
DS
Zolla-Pazner
Susan
S
D015704:CD4 Antigens / Q000502:physiology*; D054407:Chemokine CCL4; D015699:HIV Envelope Protein gp120 / Q000502:physiology; D006801:Humans; D019410:Interleukin-16 / Q000502:physiology; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D019713:Receptors, CCR5 / Q000502:physiology*; D015398:Signal Transduction
D015704:CD4 Antigens; D054407:Chemokine CCL4; D015699:HIV Envelope Protein gp120; D019410:Interleukin-16; D019402:Macrophage Inflammatory Proteins; D019713:Receptors, CCR5