Signaling in Effector Lymphocytes: Insights toward Safer Immunotherapy

Abstract

Receptors on T and NK cells systematically propagate highly complex signaling cascades that direct immune effector functions, leading to protective immunity. While extensive studies have delineated hundreds of signaling events that take place upon receptor engagement, the precise molecular mechanism that differentially regulates the induction or repression of a unique effector function is yet to be fully defined. Such knowledge can potentiate the tailoring of signal transductions and transform cancer immunotherapies. Targeted manipulations of signaling cascades can augment one effector function such as antitumor cytotoxicity while contain the overt generation of pro-inflammatory cytokines that contribute to treatment-related toxicity such as "cytokine storm" and "cytokine-release syndrome" or lead to autoimmune diseases. Here, we summarize how individual signaling molecules or nodes may be optimally targeted to permit selective ablation of toxic immune side effects.

Keywords: NK and T cells; NKG2D; immunotherapy; signaling; target molecules.

Figure 1

Activating and co-stimulatory receptors in T and NK cells and their corresponding ligands. Schematic representation of activating receptors on T cells and NK cells. While T cell receptor (TCR) functions as the primary receptor on T cells, NKG2D and CD137 function as co-stimulatory receptors along with CD28. Whereas, in NK cells, NKG2D, CD137, LY49D, NCR1, and 2B4 function as independent activating receptors and a cumulative effect of their engagement determines the final outcome of NK cell effector functions. The differences in the cytoplasmic domain of these receptors contribute to the interaction of various adapter molecules. These differences govern the signaling cascade that is engaged downstream of these receptors.

Figure 2

Receptor interacting and nucleating signaling molecules that regulate the effector functions. A graphical rendering of membrane proximal signaling events and resultant involvement of scaffold proteins, adapter molecules, and second messengers that are critical for eliciting effector functions such as cytotoxicity and proinflammatory cytokine production following NKG2D-mediated activation in NK cells.

Figure 3

Unique amino acid motifs in ADAP scaffold facilitate its interactions with multiple-binding partners. Pictorial depiction of ADAP protein and its amino acid sequences (or motifs) that are required to interact with Fyn, Carma1, TAK1, SLP76, and SKAP55. Amino acid sequences within ‘’ are from ADAP with the name of the interacting partner listed above or below this sequence.