- Tam JM, ReedyJL, Lukason DP, Kuna SG, Acharya M, Khan NS, Negoro PE, Xu S, Ward RA, Feldman MB, Dutko RA, Jeffery JB, Sokolovska A, Wivagg CN, Lassen KG, Le Naour F , Matzaraki V, Garner EC, Xavier RJ, Kumar V, van de Veerdonk FL, Netea MG, Miranti CK, Mansour MK,and Vyas JM. Tetraspanin CD82 organises Dectin 1 into signaling domains to mediate cellular response to Candida albicans. Journal of Immunology 2019 Jun e1;202(11):3256-3266. doi: 10.4049/jimmunol.1801384
- Raso F, Sagadiev S, Du S, Gage E, Arkatkar T, Metzler G, Stuart LM, Orr MT, Rawlings D, Jackson S, Lacy-Hulbert A, Acharya M. αv integrins regulate germinal center B cell responses through noncanonical autophagy. Journal of Clinical Investigations. 2018. Jul 12. Pii99597 doi 10.1172/JCI99597[E-pub ahead of print]
In this paper we show that αv and noncanonical autophagy limit the ability of germinal center (GC) B cells to respond to foreign antigens and pathogens containing TLR ligands. Loss of this regulatory break in mice, through B cell specific deletion of αv, augments GC-dependent production of affinity-matured antibodies as well as generation of memory B cells and long-lived plasma cells, in response to viral antigens and influenza virus. Our data point to targeting αv integrins as a potential strategy for enhancing GC B cell responses to vaccines.
*This paper was accompanied by an associated commentary
- Acharya M, Sokolovska A, Tam J, Conway K, Stefani C, Mukophadyaya S, Feliu M, Paul E, Hynes RO, Xavier R, Vyas J, Stuart LM , Lacy-Hulbert A. αv Integrins combine with LC3 and atg5 to regulate Toll-like Receptor signaling in B cells Nature Communications, 2016 March, 7:10917. PMCID: PMC4792966).
In this work we discovered a new role for v integrins and autophagy proteins in limiting B cell TLR signaling by regulating intracellular trafficking events. Upon B cell activation by TLRs , v integrin signalling activates autophagy proteins LC3 and Atg5 via the src and syk kinases. These autophagy proteins then determine the type and duration of TLR signaling and also terminate TLR signaling by coordinating endosomal localisation of TLRs. In B cell that lack v integrins the activation of autophagy proteins is disrupted and TLRs localise longer in early endosomal compartments resulting in enhanced TLR signaling. In mice, loss of this v-autophagy pathway specifically in B cells, results in enhanced B cell activation by TLR ligands and increased antibody production in response to antigens containing TLR ligands. This work has important implications for understanding the molecular mechansims that regulate immune response to self-derived TLR ligands in autoimmunity as well as for understanding, how B cell process antigens from pathogens such as viruses.
- Tam JM, Mansour MK, Acharya M, Sokolovska A, Timmons AK, Lacy-Hulbert A and Vyas JM. (2016) The role of autophagy-related proteins in Candida albicans infections Pathogens, 2016 Mar 29;5(2). pii: E34. doi: 10.3390/pathogens5020034.
- Tam JM, Mansour MK, Khan NS, Seward M, Puranam S, Tanne A, Sokolovska A, Becker CE, Acharya M, Baird MA, Choi AM, Davidson MW, Segal BH, Lacy-Hulbert A, Stuart LM, Xavier RJ, Vyas JM. Dectin-1-dependent LC3 recruitment to phagosomes enhances fungicidal activity in macrophages. Journal of Infectious Diseases. 2014 Dec 1;210(11):1844-54. PMCID: PMC4271056.
(featured on cover).
- Overstreet MG, Gaylo A, Angermann BR, Hughson A, Hyun YM, Lambert K, Acharya M, Billroth-Maclurg AC, Rosenberg AF, Topham DJ, Yagita H, Kim M, Lacy-Hulbert A, Meier-Schellersheim M, Fowell DJ. Inflammation-induced interstitial migration of effector CD4(+) T cells is dependent on integrin alphaV. Nature Immunology. 2013 Sep;14(9):949-58. PMCID: PMC4159184.
- Edkins AL, Borland G, Acharya M, Cogdell RJ, Ozanne BW, Cushley W. Differential regulation of monocyte cytokine release by αV and β2 integrins that bind CD23. Immunology. 2012 Jun;136(2):241-51.
- Paidassi H, Acharya M, Zhang A, Mukhopadhyay S, Kwon M, Chow C, Stuart LM, Savill J, Lacy-Hulbert A. Preferential expression of integrin αvβ8 promotes generation of regulatory T cells by mouse CD103+ dendritic cells. Gastroenterology. 2011 Nov;141(5):1813-20. PMCID: PMC3202651.
- Acharya M, Mukhopadhyay S, Paidassi H, Jamil T, Chow C, Kissler S, Stuart LM, Hynes RO, Lacy-Hulbert A. alphav Integrin expression by DCs is required for Th17 cell differentiation and development of experimental autoimmune encephalomyelitis in mice. Journal of Clinical Investigations. 2010 Dec;120(12):4445-52. PMCID: PMC2993596.
In this paper we showed that αvβ8 integrin on dendritic cells (DCs) was required during DC and T cell interaction for local activation of TGFβ and subsequent generation of Th17 cells. As a result, mice that lacked αv could not generate Th17 cells and were completely protected from Th17 mediated disease such as EAE which is a mouse model for human Multiple Sclerosis (MS). Another major significance of this work was the finding that peptide inhibitors of αv integrins could block differentiation of Th17 cells in vitro and in vivo establishing a therapeutic role for αv integrins in MS.
*This paper was featured on cover with an associated commentary and was also reviewed by Faculty of 1000
- Paidassi H, Acharya M, Lacy-Hulbert A. Alpha (v) integrins license regulatory T cells to apoptotic cells and self-associated antigens. Ann N Y Acad Sci. 2010 Oct;1209:68-76.
- Acharya M, Borland G, Edkins AL, Maclellan LM, Matheson J, Ozanne BW, Cushley W. CD23/FcεRII: molecular multi-tasking. Clin Exp Immunol. 2010 Oct;162(1):12-23. PMCID: PMC2990925.
- Acharya M, Edkins AL, Ozanne BW, Cushley W. SDF-1 and PDGF enhance αVβ5-mediated ERK activation and adhesion-independent growth of human pre-B cell lines. Leukemia. 2009 Oct;23(10):1807-17.
This paper established the importance of αvβ5-CD23 interaction during human B cell development and in B cell leukemias. We showed that chemokines and cytokines such as SDF-1 and PGDF enhanced αvβ5-CD23 induced proliferation and signaling in early B cell precursors. This work was also the first to show that this interaction was important for the growth of B cells from patients with acute lymphoblastic leukemia (ALL). By providing the mechanism of action for the role of αvβ5 in normal and malignant B cells this work has identified αv integrins as new therapeutic target in B cell leukemias.
- Borland G, Edkins AL, Acharya M, Matheson J, White LJ, Allen JM, Bonnefoy JY, Ozanne BW, Cushley W. αVβ5 integrin sustains growth of human pre-B cells through an RGD-independent interaction with a basic domain of the CD23 protein. Journal of Biological Chemistry. 2007 Sep 14;282(37):27315-26.