CD8+ T Cells and NK Cells: Parallel and Complementary Soldiers of Immunotherapy

Abstract

CD8⁺ T cells and NK cells are both cytotoxic effector cells of the immune system, but the recognition, specificity, sensitivity, and memory mechanisms are drastically different. While many of these topics have been extensively studied in CD8⁺ T cells, very little is known about NK cells. Current cancer immunotherapies mainly focus on CD8⁺ T cells, but have many issues of toxicity and efficacy. Given the heterogeneous nature of cancer, personalized cancer immunotherapy that integrates the power of both CD8⁺ T cells in adaptive immunity and NK cells in innate immunity might be the future direction, along with precision targeting and effective delivery of tumor-specific, memory CD8⁺ T cells and NK cells.

Figure 1. (A). T Cell Recognition and Signaling

The TCR and CD8 bind a pMHC presented on the antigen-presenting cell surface, causing the phosphorylation of the ITAMs of the CD3 (γ, δ, ε and ζ) chains by Lck, a tyrosine kinase associated with the coreceptor CD8. The tyrosine kinase ZAP-70 is then recruited to CD3 by binding to the phosphorylated ITAMs, leading to the phosphorylation of ZAP-70 by Lck. The activated ZAP-70 then phosphorylates LAT. Activation of LAT leads to extensive cellular adjustments, including proliferation, metabolic changes, cytolytic activity, cytokine release, and others. (B). NK Cell Recognition and Signaling. NK cell surface activating and inhibitory receptor-ligand interactions mediate the recognition and signaling of an NK cell. Some receptors present on each NK cell are stochastic, whereas others such as NKp46 and NKG2D are constitutive. The combinatorial threshold that must be reached to activate or inactivate the NK cell is largely unknown.

Figure 2. (A). Activating (+) and inhibitory (−) Cell Surface Molecules of CD8⁺ T Cells

The TCR is responsible for antigen recognition. CD8 is a co-receptor to aid TCR antigen recognition. Fc Receptors (FcRs) are so named for being glycoproteins that bind the constant (Fc) region of immunoglobulins and transducing a signal. The Greek nomenclature denotes the class of immunoglobulin (α, γ, and ε,). Costimulatory and coinhibitory molecules are accessory molecules that enhance or diminish, respectively, the signal of the TCR. Adhesion molecules assist in bringing the target cell into tight contact with the CD8⁺ T cell. Chemokine receptors are G-protein coupled receptors (GPCRs) involved in chemotactic pathways such as migration and adhesion. These receptors are so named based on how many non-conserved residues separate the binding cysteines: CCR have two adjacent cysteines, whereas CX3CR have three residues between the two cysteines. Many of the receptors indicated here denote an entire family (e.g. CCR represents CCR1-8, differentially expressed on CD8⁺ subsets); all of these receptors have multiple possible ligands. Abbreviations: CD (Cluster of Differentiation); IL-_R (Interleukin _ Receptor); LFA (Leukocyte Function-Associated Antigen); CTLA (Cytotoxic T-Lymphocyte-Associated); KIR (Killer Immunoglobulin-like Receptor); PD (Programmed Death); TNFR (Tumor Necrosis Factor Receptor). (B). Activating (+) and Inhibitory (−) Cell Surface Molecules of NK Cells. NK cells express an array of activating and inhibitory receptors for recognition. Ly49 and KIR receptors are hypothesized to be a result of convergent evolution due to the presence of immunoreceptor tyrosine-based activation/inhibitor motifs (ITAMs/ITIMs, respectively). The KIR ligands are particular HLA molecules only expressed on distressed cells. Abbreviations: H (Human); M (Murine); GM-CSFR (Granulocyte Macrophage Colony Stimulating Factor Receptor); HLA (Human Leukocyte Antigen); MIC (MHC Class I Chain- related); HA (Hemagluttinin); PILR (Paired Ig-like Receptor); LILR (Leukocyte Immunoglobulin-like Receptor); KLRG1 (Killer Cell Lectin-like Receptor G1).