ABSTRACT
Activation of naïve T cells requires synergistic signals produced by the T-cell receptor (TCR) and by CD28. We previously identified the novel adaptor ALX, which, upon overexpression in Jurkat T cells, inhibited activation of the interleukin-2 (IL-2) promoter by TCR/CD28, suggesting
that it is a negative regulator of T-cell activation. To further
understand the physiological role of ALX, ALX-deficient mice were
generated. Purified T cells from ALX-deficient mice demonstrated
increased IL-2 production, CD25 expression, and proliferation in
response to TCR/CD28 stimulation. Enhanced IL-2 production and
proliferation were also observed when ALX-deficient mice were primed in
vivo with ovalbumin-complete Freund's adjuvant and then restimulated ex
vivo. Consistent with our initial overexpression studies, these data
demonstrate that ALX is a negative regulator of T-cell activation.
While TCR/CD28-mediated activations of phosphotyrosine induction,
extracellular signal-regulated kinase 1/2, Jun N-terminal protein
kinase, IκB kinase α/β, and Akt
were unaltered, constitutive activation of p38 mitogen-activated
protein kinase and its upstream regulators MKK3/6 were observed for
ALX-deficient splenocytes. The phenotype of ALX-deficient mice
resembled the phenotype of those deficient in the transmembrane adaptor
LAX, and an association between ALX and LAX proteins was demonstrated.
These results suggest that ALX, in association with LAX, negatively
regulates T-cell activation through inhibition of
p38.