CD152 (CTLA-4) Determines CD4 T Cell Migration In Vitro and In Vivo

Abstract

BackgroundMigration of antigen-experienced T cells to secondary lymphoid organs and the site of antigenic-challenge is a mandatory prerequisite for the precise functioning of adaptive immune responses. The surface molecule CD152 (CTLA-4) is mostly considered as a negative regulator of T cell activation during immune responses. It is currently unknown whether CD152 can also influence chemokine-driven T cell migration.Methodology/Principal FindingsWe analyzed the consequences of CD152 signaling on Th cell migration using chemotaxis assays in vitro and radioactive cell tracking in vivo. We show here that the genetic and serological inactivation of CD152 in Th1 cells reduced migration towards CCL4, CXCL12 and CCL19, but not CXCL9, in a G-protein dependent manner. In addition, retroviral transduction of CD152 cDNA into CD152 negative cells restored Th1 cell migration. Crosslinking of CD152 together with CD3 and CD28 stimulation on activated Th1 cells increased expression of the chemokine receptors CCR5 and CCR7, which in turn enhanced cell migration. Using sensitive liposome technology, we show that mature dendritic cells but not activated B cells were potent at inducing surface CD152 expression and the CD152-mediated migration-enhancing signals. Importantly, migration of CD152 positive Th1 lymphocytes in in vivo experiments increased more than 200% as compared to CD152 negative counterparts showing that indeed CD152 orchestrates specific migration of selected Th1 cells to sites of inflammation and antigenic challenge in vivo.Conclusions/SignificanceWe show here, that CD152 signaling does not just silence cells, but selects individual ones for migration. This novel activity of CD152 adds to the already significant role of CD152 in controlling peripheral immune responses by allowing T cells to localize correctly during infection. It also suggests that interference with CD152 signaling provides a tool for altering the cellular composition at sites of inflammation and antigenic challenge.

Murine regulatory T cells differ from conventional T cells in resisting the CTLA-4 reversal of TCR stop-signal

“…8,21,22 The effect on motility and migration has now been reported by several other groups. [25][26][27] In this study, we reveal a clear difference in CTLA-4 modulation of the contact times and motility of Tconvs relative to Tregs. This was shown in several assays including the finding that CTLA-4 ligation reversed the anti-CD3 induced stop-signal on FoxP3-negative cells at concentrations that had no effect on FoxP3-positive Tregs, and that the presence of CTLA-4 reduced the contact times of DO11.10 x CD4 ϩ CD25 Ϫ Tconvs, but not DO11.10 x CD4 ϩ CD25 ϩ Tregs, with OVA presenting DCs in lymph nodes.…”

“…8,21,22 Reduced contact times by CTLA-4 would be expected to limit TCR ligation events and raise the threshold for T-cell activation. [21][22][23][24] The motility inducing effects of CTLA-4 have been confirmed by several laboratories in various in vivo models, [25][26][27] and involves CTLA-4 activation of the GTP binding protein Rap1 and LFA-1 adhesion. 24,28 Immune responses are regulated by a balance of inflammatory responses by conventional or responder T cells (Tconvs) and suppression by Tregs that maintain tolerance to self-antigen.…”

Blockade of CTLA-4 Decreases the Generation of Multifunctional Memory CD4+ T Cells In Vivo

“…Absence of CTLA-4 engagement during Ag priming leads to enhanced cytokine production (18)(19)(20). Moreover, CTLA-4 recently has been shown to mediate resistance to apoptosis in vitro, to enhance migration of CD4 + T cells in vivo (21)(22)(23)(24)(25), and to be constitutively expressed on natural regulatory T cells (nTregs) (26). Importantly, the suppressive function of nTregs is dependent on CTLA-4, which impedes activation of Ag-experienced T cells via downregulation of CD80 and CD86 on dendritic cells and induces the tryptophan catabolizing enzyme IDO (27)(28)(29).…”

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

“…We have shown that CTLA-4 facilitates critical functions of already activated T-lymphocytes: Suppression of T-cell proliferation [4] , suppression of effector functions [20,21] , induction of survival [10] and migration of T-lymphocytes [23] . Lymphocytes that receive a CTLA-4 signal are stopped in their proliferation and survive [1] .…”

“…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.…”