Research Interests
Dr. Chess who for 25 year directed the Division o Rheumatology at Columbia has pioneered in the identification and study of biologically and clinically important molecules on the surface of human T lymphocytes. An important characteristic of the Chess lab has been its ability to bring basic discoveries made at the bench to the development of drugs employed in the treatment of human immune disease. In this regard, Dr. Chess’s lab identified the structure and functions of key human T cell surface molecules (including CD4, CD8, γδTCR, CD40L, α1/β1 integrin). Some of these molecules have been employed to develop therapeutics in clinical trials of human immunologic disease: including recombinant CD4 molecules for HIV and monoclonal anti–CD40L and anti-VLA-1 for autoimmune disease and transplant rejection. Currently Dr. Chess is Director of Columbia University’s NIH designated Autoimmunity Center of Excellence (ACE). His most significant accomplishments include:

(1) The first isolation of functionally distinct human helper, cytotoxic and suppressor T cell CD4 and CD8 subsets defined by monoclonal antibodies. (initially with Dr. Stuart Schlossman);

(2) The isolation of genes encoding the CD4 and CD8 molecules (in collaboration with Dr. Richard Axel). The CD4 genes enabled experiments that definitively showed that CD4, in addition to functioning as a receptor for MHC class II, is also a HIV receptor and to clinical trials employing recombinant soluble CD4 which blocks HIV entry into cells.

(3) The first identification of the γ,δ T cell receptor molecule and isolation of γ,δ T cell clones which were shown to secrete lymphokines and potently kill tumor cells.

(4) The first identification and functional characterization of the CD40L molecule, which mediates the helper and inducer functions of T cells. The scientists and physicians in the Chess lab, including Drs. Seth Lederman and Mile Yellin demonstrated that CD40L mediates the capacity of T cells to induce B cell antibody synthesis and Ig class switching. Genetic deficiency of CD40L in man leads to the hypogammaglobulinemia associated with the hyper IgM immunodeficiency syndrome.  The first monoclonal antibodies to CD40L were developed by the Chess lab and were shown to block key events in T cell activation of B cells, macrophages and dendritic cells. In collaboration with Biogen these studies led to clinical trials to prevent or treat immune mediated disease in man including Systemic Lupus (SLE), Idiopathic thrombocytopenia purpura and transplant rejection;

(5) The Chess lab spearheaded by Dr. Ilan Bank, also created the first monoclonal antibode alpha chain of the alpha 1, beta 1 Integrin (VLA-1). These antibodies interact with VLA-1 expressed on the surface of activated T cells and block migration of cells to sites of inflammation and inhibit autoimmunity in murine disease models of RA and MS. Humanized antibodies to anti-VLA-1 are being developed Biogen for treatment of immunological disease in man.

(6) A major current focus of the Chess lab has been in the identification of a novel set regulatory CD8 T cells important in the down-regulation of autoreactive T cells involved in mediating autoimmune disease. These regulatory CD8 T cells express a,b T cell receptors that are restricted by the MHC class 1b molecules (Qa-1 in mice and HLA-E in humans). These T cell receptors recognize Qa-1 or HLA-E molecules bound with peptides expressed as a function of the avidity of T cell activation and preferentially recognize and down-regulate autoreactive T cells of intermediate avidity. Blockade of these receptors leads to exacerbated autoimmune disease. These studies led Dr. Hong Jiang to propose an avidity model of T cell regulation. The goals currently are to decipher means of inducing these regulatory cells in vivo to down-regulate autoimmunity and control and abort transplantation rejection.

Representative manuscripts covering interest areas in the Chess lab:

(1) Identification of the genes encoding CD4 and CD8 and functional analysis of CD4 and CD8 T cell subsets
Evans, R.L., Breard, J.M., Lazarus, H., Schlossman, S.F. and Chess, L. Detection, isolation and functional characterization of two human T cell subclasses bearing unique differentiation antigens. J. Exp. Med. 145: 221-233, 1977.

Maddon P.J., Littman D.R., Godfrey M., Maddon D.E., Chess L, Axel R. 1985. The isolation and nucleotide sequence of a cDNA encoding the T cell surface protein T4: a member of the immunoglobulin gene family. Cell. 42:93-104.

Littman, D.R., Thomas, Y., Maddon, P.J., Chess, L. and Axel, R. 1985. The isolation and sequence of the gene encoding T8: a molecule defining functional classes of T lymphocytes. Cell 40:237-246, 1985.

(2) Discovery and characterization of the g,d TCR
Bank, I., DePinto, R.A., Brenner, M.B., Cassimeris, J., Alt, F.W., andChess, L. A functional T3 molecule associated with a novel heterodimer on the surface of the immature human thymocytes. Nature 322(6075):179-181, 1986. (discovery of the g/d TCR)

(3) Identification and functional characterization of the human a1b1 integrin, VLA-1
Bank, I., Hemler, M., Brenner, M. B., Cohen, D. , Levy, V., Belko, J., Crouse, C. and Chess, L. A novel monoclonal Antibody, IB3.1, binds to a new epitope of the VLA-1 molecule. Cell Immunol. 122(2): 416-23, 1989.

Goldstein, I., S. Ben-Horin, J. Li, I. Bank, H. Jiang, and L. Chess. 2003. Expression of the alpha1beta1 integrin, VLA-1, marks a distinct subset of human CD4+ memory T cells. J Clin Invest 112:1444.

(4) Identification and characterization of CD40L
Lederman, S., Yellin, M.J., Krichevsky, A., Belko, J.,Lee, J.J. and L. Chess. Identification of a novel surface protein on activated CD4+ T cells that induces contact dependent B cell differentiation (Help) J. Exp. Medicine. 175(4): 1091-1101, 1992.(First identification of ÇD40L) led to patent and clinical trials

Chess, L. Blockage of the CD40L/CD40 Pathway. Therapeutic Immunology, November 2000. 441-456 (Review article of work initiated in 1991)

Karpusas, M., Y. Hsu, J. Wang, J. Thompson, S. Lederman, L. Chess, and D. Thomas. 2 Å crystal structure of an extracellular fragment of human CD40 ligand. Structure 15, October, 1995, 3:1031-1039.

(5) Immunoregulatory CD8+ T cells
Jiang, H., R. Ware, A. Stall, L. Flaherty, L. Chess, B. Pernis. Murine CD8+ T Cells that Specifically Delete Autologous CD4+ T Cells Expressing Vb8 TCR: A Role of the Qa-1 Molecule. Immunity, 1995, 2:185-194.

Jiang, H., Y. Wu, B. Liang, Z. Zheng, G. Tang, J. Kanellopoulos, M. Soloski, R. Winchester, I. Goldstein, and L. Chess. 2005. An affinity/avidity model of peripheral T cell regulation. J Clin Invest 115:302.

Jiang, H., and L. Chess. 2000. The Specific Regulation of Immune Responses by CD8+ T Cells Restricted by the MHC Class IB Molecule, Qa-1. Annu. Rev. Immunol. 18:185-216.

Jiang, H., Wu, Y., Liang, B., Zheng, Z., G., T., Kanellopoulos, J., M., S., R., W., Goldstein, I., and Chess L. 2005. An "Affinity/avidity Model of Peripheral T Cell Regulation". J. Clin. Invest. 115: 302-312.

Jiang, H., and L. Chess. 2006. Regulation of immune responses by T cells. N Engl J Med 354:1166-1176.

Chen, W., et al., Perceiving the avidity of T cell activation can be translated into peripheral T cell regulation