Migration of Th1 Lymphocytes Is Regulated by CD152 (CTLA-4)-Mediated Signaling via PI3 Kinase-Dependent Akt Activation

Abstract

Efficient adaptive immune responses require the localization of T lymphocytes in secondary lymphoid organs and inflamed tissues. To achieve correct localization of T lymphocytes, the migration of these cells is initiated and directed by adhesion molecules and chemokines. It has recently been shown that the inhibitory surface molecule CD152 (CTLA-4) initiates Th cell migration, but the molecular mechanism underlying this effect remains to be elucidated. Using CD4 T lymphocytes derived from OVA-specific TCR transgenic CD152-deficient and CD152-competent mice, we demonstrate that chemokine-triggered signal transduction is differentially regulated by CD152 via phosphoinositide 3-kinase (PI3K)-dependent activation of protein kinase B (PKB/Akt). In the presence of CD152 signaling, the chemoattractant CCL4 selectively induces the full activation of Akt via phosphorylation at threonine 308 and serine 473 in pro-inflammatory Th lymphocytes expressing the cognate chemokine receptor CCR5. Akt signals lead to cytoskeleton rearrangements, which are indispensable for migration. Therefore, this novel Akt-modulating function of CD152 signals affecting T cell migration demonstrates that boosting CD152 or its down-stream signal transduction could aid therapies aimed at sensitizing T lymphocytes for optimal migration, thus contributing to a precise and effective immune response.

Molecular mechanisms of T cell co-stimulation and co-inhibition

“…Additionally, CTLA4 ligation was found to regulate distal signalling events by inhibiting ERK and JNK phosphorylation 48 . Interestingly, the YVKM motif also binds PI3K, and it has recently been demonstrated that CTLA4 promotes CD4 + T cell migration through PI3K-dependent AKT activation 49 . Meanwhile, it remains unclear whether the CTLA4–PI3K–AKT pathway also has a co-stimulatory function.…”

The neonatal immune system: modulation by regulatory T-cells and CTLA-4 (CD152)1)

“…We have shown so far that in the CTLA-4-mediated modulation of T-cell functions, such as proliferation and cytokine production [3,4,18,20] , but also in connection with activation-induced cell death (a form of apoptosis), CTLA-4 signals interfere differentially with gene expression by inhibiting the activation of key transcription factors such as NFAT, eomesodermin, GATA3, and FKHRL1 (but not cKrox, AP1, or T-bet!). In particular, we have been able to show that CTLA-4 induces the expression of Bcl-2 and of the chemokine receptor CCR5, and activates the enzyme activity of PI3 kinase [10,11,24] .…”

“…This ensures that the immune response is stopped. In addition, T-lymphocytes that receive a CTLA-4 signal migrate along inflammatory and homeostatic chemokine gradients [23,11] . The lymphocytes surviving at the end of an immune response and migrating to memory areas might be potential precursors of memory cells.…”

“…But the membrane expression of CCR5 [24] does not allow for conclusions about migration, because chemokine receptors pass their signals on through G-proteins, which are often present in the inactive state. We set up in vitro migration experiments to analyze the specific migration of Th1 lymphocytes in vitro [23,11] . Here, the endothelium is replaced by a membrane.…”

“…Already activated T-lymphocytes are inhibited in their proliferation by CTLA-4 [4] . CTLA-4 signals also induce PI3 kinase-dependent survival in already activated T-lymphocytes, and CTLA-4 signals facilitate migration along the chemokine gradient [10,11] . Surviving lymphocytes at the end of an immune response could be precursors of memory cells.…”