KLRG1 Immune Checkpoint Molecule for Drug Development

Immune Checkpoint KLRG1

A type II transmembrane protein KLRG1(killer-cell lectin like receptor G1), has been identified as a marker for differentiation and a co-inhibitory receptor, expressed on subsets of T cells and natural killer (NK) cells.

CHECKPOINT RECEPTOR	ALTERNATE NAME	CELL TYPE AFFECTED	LIGAND	THE FUNCTION OF LIGAND-RECEPTOR INTERACTION
KLRG1	2F1; MAFA/ MAFA-LIKE/MAFA-L; CLEC15A	T cells, NK cells	E-, N-, and R-cadherin	Co-inhibition

Structure of KLRG1

KLRG1 is a homodimeric molecule composed of two 30-38 kDa N-glycosylated subunits. It is an inhibitory C-type lectin consisting of a transmembrane region, an intracellular immunoreceptor tyrosine-based inhibitory motif (ITIM) in the cytoplasmic domain, which mediates its effects through the recruitment of SHIP-1 and SHP-2 phosphatases to binds to its ligands, and a tyrosine residue at position 7 in the ITIM, and a C-type lectin-like domain in extracellular region.

Fig.1 Structure of KLRG1 bound to the membrane-distal D1 domain of E-cadherin.¹

Expression of KLRG1

KLRG1 is predominantly on late-differentiated effector and effector memory CD4⁺ T, CD8⁺ T, and terminally differentiated NK cells in lungs, spleen, and peripheral blood during normal development. The expression level of KLRG1 on T cells and NK cells can be induced during viral and bacterial responses.

Functions of KLRG1

KLRG1 binds to E-, N-, and R-cadherin and mediates its effects to regulate effector functions and developmental processes. The expression of KLRG1 has been found to increase with age and differentiation and can be used to identify memory precursor cells from effector T cells. More than acting as a marker of differentiation, the ITIM in its cytoplasmic domain indicates that it may play a functional role in the immune system. Previous studies have revealed that KLRG1 inhibits NK cytotoxicity, antigen-induced proliferation, and induction of the cytolytic activity of CD8 T cells. KLRG1 may also have an essential role in monitoring and removing cancer cells that lose E-cadherin expression.

KLRG1 Immune Checkpoint Molecule for Drug Development

Targeting of other co-inhibitory receptors for applications for drug development has drawn widespread attention, while the therapeutic potential of KLRG1 modulation has been focused less relatively. Still, there are studies demonstrating that an anti-KLRG1 antibody can increase ex vivo human NK cell interferon-gamma secretion. Another research has found that anti-E-cadherin antibodies can result in enhanced ex vivo human CD8⁺ T cell proliferation and NK cell cytotoxicity, leaving opportunities for KLRG1 in human CD8⁺ T cell activation. There are also anti-KLRG1 depleter and anti-KLRG1 blocker drugs under pre-clinical trials currently, against multiple autoimmune indications, myeloma, or solid tumors.

Services at Creative Biolabs

With sufficient experience and proven R & D capabilities, Creative Biolabs provides professional immune checkpoint drug development services. Our technology platforms offer a full range of KLRG1 immune checkpoint molecule drug development services, including but not limited to:

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Reference

Rangarajan, et al. "Natural Killer Cell Receptors." Structural Biology in Immunology. Academic Press, 2018. 101-125.

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