Mass General Hospital

LAB MISSION:

To understand the impact of leukocyte trafficking in gastrointestinal and systemic immunity and its implications for normal and pathological immune responses.

LAB RESEARCH FOCUS:

Lymphocyte migration is essential for both normal and pathological immune responses. In order to accomplish their effector/regulatory function, lymphocytes must leave the blood and reach different tissue compartments in the body. A critical step in this process is the adhesion and transmigration of lymphocytes through the endothelial barrier in postcapillary venules. This is a strictly regulated process that occurs in sequential steps, which have been partially characterized. Whereas naive T cells express homing receptors allowing them to migrate to all secondary lymphoid organs (lymph nodes, Peyer's patches and the spleen), they are normally excluded from non-lymphoid peripheral tissues. However, once T cells are activated by their cognate antigen, they change their pattern of adhesion receptors and acquire the capacity to migrate to extralymphoid tissues.

Since the intestinal mucosa and the skin are the largest body surfaces in contact with the external environment, it is critical to understand how lymphocytes migrate into these tissues in order to confer proper protection against pathogens. It has been demonstrated that lymphocytes need the integrin 7 and the chemokine receptor CCR9 in order to migrate to the small intestine lamina propria. On the other hand, lymphocyte homing to the skin requires ligands for E- and P-selectin and the chemokine receptor CCR4 and/or CCR10. Summarizing, the expression of gut- and skin-homing receptors establishes a dichotomy in the distribution of effector/memory T cells, compartmentalizing the immune responses into two major body surface areas exposed to antigens (Trends Immunol., 27: 235, 2006).

However, a fundamental question is how lymphocytes acquire this differential tissue-specific migratory capacity after they are activated. We hypothesized that dendritic cells (DC, cells in charge of presenting antigens and activating T cells), "instruct" T cells in tissue-specific migratory potential upon activation. Indeed, we demonstrated that DC from gut-associated lymphoid tissues (GALT-DC), but not from other lymphoid compartments, efficiently imprint T cells with intestinal tropism (Nature, 347: 88, 2003). This work showed for the first time that DC act as a unique tissue element conferring tissue-specific migratory potential to T cells, highlighting a completely new function for DC, distinct from their well-known role in T cell activation. Moreover, we found that this paradigm also applies to the skin because DC associated with cutaneous lymph nodes induce skin-tropism on T cells. In addition, we demonstrated that already committed gut- or skin-tropic effector/memory T cells exhibit plasticity and therefore can be "re-educated" by DC to change their migratory potential (J. Exp. Med, 201: 303, 2005). More recently, we have shown that, similar to T cells, the other branch of the adaptive immune system, namely B cells and antibody secreting cells, are also imprinted with gut-tropism by GALT-DC in a mechanism dependent on the vitamin A metabolite retinoic acid (RA). Importantly, we showed that the mechanisms imprinting gut homing lymphocytes are completely conserved between mice and humans (Science, 314: 1157, 2006). Thus, GALT-DC and RA shape gut immunity by modulating T and B cell migration as well as IgA secretion.

Current lines of work in our lab are:

1. How GALT-DC are themselves "educated" in the gut to acquire their remarkable capacity to imprint lymphocytes with gut-tropism and IgA-secreting capacity.
2. The intersection between the mechanisms inducing gut-homing and those inducing IgA-secreting cells.
3. The role of gut-homing during gut inflammation and cancer.
4. How T and B lymphocytes are "imprinted" to home to other mucosal compartments, such as colon and lungs.
5. The hypothesis that gut-homing and oral immunological tolerance are interrelated.
6. The role of tissue-specific T cell migration in the establishment of immunological memory.

Ultimately, we expect that our research will provide new insights into the mechanisms regulating the migration of effector/memory lymphocytes under normal as well as pathological conditions, with the possibility of suggesting new therapeutic avenues.

Selected Publications:

• J. Rodrigo Mora, M. Rosa Bono, N. Manjunath, Wolfgang Weninger, Lois Cavanagh, Mario Rosemblatt & Ulrich H. von Andrian. Selective Imprinting of Gut-Homing T Cells by Peyer's Patch Dendritic Cells. Nature. 424: 88-93 (2003).


• J. Rodrigo Mora, Guiying Cheng, Dominic Picarella, Michael Briskin, Natasha Buchanan & Ulrich H. von Andrian. Reciprocal and Dynamic Control of CD8 T Cell Homing by Dendritic Cells from Skin- and Gut-Associated Lymphoid Tissues. J. Exp. Med. 201: 303-316 (2005).


• J. Rodrigo Mora & Ulrich H. von Andrian. T Cell Homing Diversity and Plasticity: Emerging Platforms for Therapeutic Immunomodulation. Trends Immunol., 27: 235-243 (2006).


• J. Rodrigo Mora, Makoto Iwata, Bertus Eksteen, Si-Young Song, Tobias Junt, Balimkiz Senman, Kevin L. Otipoby, Aya Yokota, Hajime Takeuchi, Paola Ricciardi-Castagnoli, Klaus Rajewsky, David H. Adams & Ulrich H. von Andrian. Generation of gut-homing IgA-secreting cells by intestinal dendritic cells. Science, 314: 1157-1160 (2006).


• J. Rodrigo Mora. Homing Imprinting and Immunomodulation in the Gut: Role of Dendritic Cells and Retinoids. Inflamm. Bowel Dis., 14: 275-289 (2008).


• J. Rodrigo Mora & Ulrich H. Von Andrian. Differentiation and Homing of IgA-Secreting Cells. Mucosal Immunology, 1: 96-109 (2008).


• Eduardo J. Villablanca, Vincenzo Russo & J. Rodrigo Mora. Dendritic cell migration and lymphocyte homing imprinting. Histol. Histopathol., 23: 897-910 (2008).


• J. Rodrigo Mora, Makoto Iwata & Ulrich H. Von Andrian. Vitamins Effects on the Immune System: Vitamins A and D Take Center Stage. Nature Rev. Immunol., (2008) In press.

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