Caveolin-1 Is Required For T Cell-Mediated Acute GvHD

Caveolin-1 (Cav-1) is a key organizer of membrane specializations that coordinate membrane and protein traffic in different cells including T cells. Cav-1 promotes the formation and stability of plasma membrane raft microdomains that serve as platforms for signal transduction and binds a wide array of signal transducers through interactions with its phosphorylated tyrosine 14 or the so-called scaffolding domain. Several of the proteins identified as Cav-1 binding partners have been suggested to play a role in TCR-regulated membrane dynamics and intracellular signaling. Therefore, we aimed to determine the requirement of Cav-1 for T cells during acute graft-versus-host disease (GvHD).

We observed upregulation of Cav-1 in the T cells of mice developing acute GvHD which was dependent on both tissue damage and homeostatic signals as investigated in conditioned WT recipients or RAG-/-C gamma chain-/- non-conditioned mice. By using gene targeted mice we found that Cav-1 deficiency of the donor led to improved survival (p=0.02), lower GvHD histopathology scores (p=0.004) and reduced serum levels of IL-6 (p=0.02) while Treg numbers increased when Cav-1 deficient donors were used. Comparative microarray analysis of WT compared to Cav-1 deficient T cells indicated a reduced IL-17A production in Cav-1 T cells exposed to allogeneic dendritic cells. These observations were confirmed on the protein level.

In summary we show a role for Cav-1 in T cells during GvHD as an alloantigen driven T cell response. Regarding the mechanism we describe the relevance of Cav-1 for Th-17 lineage commitment of alloreactive T cells during GvHD.