Our laboratory is engaged in experimental studies of the human NKG2D lymphocyte receptor and  its ligands, and the mechanisms whereby these proteins stimulate or suppress immune responses against cancer and in autoimmune disease. The NKG2D-DAP10 receptor signaling complex and its ligands embody an 'induced-self' paradigm of lymphocyte activation: NKG2D triggers natural killer (NK) cells and stimulates T cells after engaging ligands that are induced by viral transactivation or cellular stress in cells that are compromised by infection, malignancy, or autoimmune disease. Human NKG2D ligands are distant relatives of major histocompatibility complex (MHC) class I molecules and include the closely related MICA and MICB and the ULBP1-ULBP3 and RAET1E and RAET1G glycoproteins. Among these ligands, at least MICA is frequently associated with epithelial tumors and certain tissues affected by inflammation or autoimmune disease such as rheumatoid arthritis synovia. Binding of MICA to NKG2D thus promotes NK cell and CD8 T cell-mediated tumor destruction but exacerbates autoimmune disease severity by stimulation of autoreactive and proinflammatory NKG2D+ CD4 T cells.

A prominent role of NKG2D and its ligands in the immune defense against cancer is generally recognized. However, cancers adopt diverse strategies for immune evasion to safeguard their survival. Many progressing tumors shed soluble MICA, which induces internalization and degradation of NKG2D in NK cells and CD8 T cells, thereby impairing their ability to attack. Moreover, sustained tumor expression and shedding of MICA stimulate proliferative expansions of an unconventional subset of NKG2D+ CD4 T cells that have immunosuppressive effects. Functionally equivalent T cells inversely correlate with disease activity in systemic lupus erythematosus (SLE),  thus suggesting that they participate in the regulation of effector responses that provoke autoimmunity.

Our current research is focused on the expression and regulation of NKG2D and its ligands and on the mechanism of tumor shedding of MICA, which involves domain remodeling by a cell surface protein disulfide isomerase called ERp5. We are studying the development of the suppressive NKG2D+ CD4 T cells and seek to identify self-antigens that they recognize. The significance and regulatory functions of these T cells are being further explored in pathologies other than those examined so far. Observations suggesting that exposure to NKG2D ligands can result in T cell functional imprinting by an unusual NKG2D-independent mechanism are also pursued.

MHC class I-like structure of the stress-inducible NKG2D ligand MICA (courtesy of Dr. Roland Strong)
Expression of MICA in renal cell carcinoma (bottom) but not in normal kidney tissue (top)
MICA on rheumatoid arthritis synoviocytes stimulates autoreactive responses by CD4 T cells with cytokine-induced NKG2D expression
NKG2D receptor homodimers are associated with DAP10 adaptor proteins, which activate signaling pathways for cytotoxicity and cytokine production

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