Antonin de Fougerolles

The Collagen Binding α1β1 Integrin VLA-1 Regulates CD8 T Cell-Mediated Immune Protection against Heterologous Influenza Infection

A common feature of many infections is that many pathogen-specific memory T cells become established in diverse nonlymphoid tissues. A mechanism that promotes the retention and survival of the memory T cells in diverse tissues has not been described. Our studies show that the collagen binding α1β1 integrin, VLA-1, is expressed by the majority of influenza-specific CD8 T cells recovered from nonlymphoid tissues during both the acute and memory phases of the response. Antibody treatment or genetic deficiency of VLA-1 decreased virus-specific CTL in the lung and other nonlymphoid tissues, and increased them in the spleen. In spite of the increase in the spleen, secondary heterosubtypic immunity against flu was compromised. This suggests that VLA-1 is responsible for retaining protective memory CD8 T cells in the lung and other tissues via attachment to the extracellular matrix.

|[alpha]|1|[beta]|1 integrin is crucial for accumulation of epidermal T cells and the development of psoriasis

Psoriasis is a common T cell–mediated autoimmune inflammatory disease. We show that blocking the interaction of α1β1 integrin (VLA-1) with collagen prevented accumulation of epidermal T cells and immunopathology of psoriasis. α1β1 integrin, a major collagen-binding surface receptor, was exclusively expressed by epidermal but not dermal T cells. α1β1-positive T cells showed characteristic surface markers of effector memory cells and contained high levels of interferon-γ but not interleukin-4. Blockade of α1β1 inhibited migration of T cells into the epidermis in a clinically relevant xenotransplantation model. This was paralleled by a complete inhibition of psoriasis development, comparable to that caused by tumor necrosis factor-α blockers. These results define a crucial role for α1β1 in controlling the accumulation of epidermal type 1 polarized effector memory T cells in a common human immunopathology and provide the basis for new strategies in psoriasis treatment focusing on T cell–extracellular matrix interactions.

A Role for the Lymphotoxin/LIGHT Axis in the Pathogenesis of Murine Collagen-Induced Arthritis

A lymphotoxin-β (LTβ) receptor-Ig fusion protein (LTβR-Ig) was used to evaluate the importance of the lymphotoxin/LIGHT axis in the development and perpetuation of arthritis. Prophylactic treatment with the inhibitor protein LTβR-Ig blocked the induction of collagen-induced arthritis in mice and adjuvant arthritis in Lewis rats. Treatment of mice with established collagen-induced arthritis reduced the severity of arthritic symptoms and joint tissue damage. However, in a passive model of anti-collagen Ab-triggered arthritis, joint inflammation was not affected by LTβR-Ig treatment precluding LT/LIGHT involvement in the very terminal immune complex/complement/FcR-mediated effector phase. Collagen-II and Mycobacterium-specific T cell responses were not impaired, yet there was evidence that the overall response to the mycobacterium was blunted. Serum titers of anti-collagen-II Abs were reduced especially during the late phase of disease. Treatment with LTβR-Ig ablated follicular dendritic cell networks in the draining lymph nodes, suggesting that impaired class switching and affinity maturation may have led to a decreased level of pathological autoantibodies. These data are consistent with a model in which the LT/LIGHT axis controls microenvironments in the draining lymph nodes. These environments are critical in shaping the adjuvant-driven initiating events that impact the subsequent quality of the anti-collagen response in the later phases. Consequently, blockade of the LT/LIGHT axis may represent a novel approach to the treatment of autoimmune diseases such as rheumatoid arthritis that involve both T cell and Ab components.

Importance of Innate Immunity and Collagen Binding Integrin α1β1 in TNBS-Induced Colitis

Inflammation occurs in the context of integrin-mediated adhesive interactions of cells with their extracellular matrix environment. We investigated the role of the collagen binding integrin alpha1beta1 in a model of colitis. alpha1beta1 was expressed on lamina propria T cells and monocytes during disease. Both alpha1 deficiency and anti-alpha1 mAb treatment (prophylactic and therapeutic) protected against colitis. In vivo alpha1beta1 blockade improved macroscopic and histologic scores, decreased inflammatory cytokine production, and profoundly affected the ability of lamina propria mononuclear cells to proliferate and produce IFN-gamma in vitro. Development and alpha1-mediated inhibition of colitis can be lymphocyte independent, suggesting that activated monocytes also represent a key alpha1beta1-expressing cell type involved in colitis. These results underscore the importance of innate immunity and, specifically, of leukocyte/matrix interactions in regulating local inflammatory responses.

Reprograming T cells: the role of extracellular matrix in coordination of T cell activation and migration

The stable immunological synapse between a T cell and antigen-presenting cell coordinates migration and activation. Three-dimensional collagen gels transform this interaction into a series of transient hit-and-run encounters. Here we integrate these alternative modes of interaction in a model for primary T cell activation and effector function in vivo.

Expression and Functional Importance of Collagen-Binding Integrins, α1β1 and α2β1, on Virus-Activated T Cells

Adhesive interactions are crucial to cell migration into inflammatory sites. Using murine lymphocytic choriomeningitis virus as an Ag model system, we have investigated expression and function of collagen-binding integrins, α1β1 and α2β1, on activated and memory T cells. Using this system and MHC tetramers to define Ag-specific T cells, we demonstrate that contrary to being VLAs, expression of α1β1 and α2β1 can be rapidly induced on acutely activated T cells, that expression of α1β1 remains elevated on memory T cells, and that expression of α1β1 parallels that of viral-specific effector CD8+ T cells (defined by tetramer and IFN-γ staining). In an adoptive transfer model, mAb-mediated blockade of these integrins on activated effector and memory T cells inhibited Ag-specific delayed-type hypersensitivity responses; similar decreased responses were seen upon transfer of α1-deficient activated/memory T cells. Thus, expression of α1β1 and α2β1 integrins on activated T cells is directly functionally important for generation of inflammatory responses within tissues. Finally, the inhibitory effect of α1β1 blockade on the delayed-type hypersensitivity response could be bypassed by direct injection of Ag-specific T cells to inflammatory sites, demonstrating for the first time in vivo that collagen-binding integrins are involved in leukocyte migration into tissues.

Regulation of monocyte gene expression by the extracellular matrix and its functional implications

Summary: By binding to extracellular matrix (ECM) proteins, integrins integrate signals from outside the cell and transmit them inwards, thereby providing cells with information about location and allowing them to respond to stimuli in a manner appropriate to their environment. This is particularly important for monocytes and macrophages, given their wide distribution throughout the body and the vital role they play in immune and inflammatory responses. Integrin‐mediated interaction of monocytes with ECM is a potent regulator of gene expression and is strongly synergized by the presence of growth factors. This synergy between growth factors and integrins is also apparent in the overlap seen in their signaling pathways. Integrin‐mediated interaction with ECM results in increased expression of numerous inflammatory and immune response genes, revealing an important role for ECM–integrin interaction in affecting monocyte function and thus impacting on the development of pathologies. This is of particular relevance in the context of immune and inflammatory responses, where integrin‐mediated adhesive interactions with the ECM‐rich peripheral tissues are central to the localization of both resident and infiltrating monocytes at inflammatory sites. Here, we will review the functional effects of integrin–ECM interactions on monocytes, with particular attention to the regulation of gene expression by ECM and its functional implications.