Plasticity in programming of effector and memory CD8 T-cell formation

Abstract

CD8(+) T cells (also called cytotoxic T lymphocytes) play a major role in protective immunity against many infectious pathogens and can eradicate malignant cells. The path from naive precursor to effector and memory CD8(+) T-cell development begins with interactions between matured antigen-bearing dendritic cells (DCs) and antigen-specific naive T-cell clonal precursors. By integrating differences in antigenic, costimulatory, and inflammatory signals, a developmental program is established that governs many key parameters associated with the ensuing response, including the extent and magnitude of clonal expansion, the functional capacities of the effector cells, and the size of the memory pool that survives after the contraction phase. In this review, we discuss the multitude of signals that drive effector and memory CD8(+) T-cell differentiation and how the differences in the nature of these signals contribute to the diversity of CD8(+) T-cell responses.

Fig. 1. Activation of antigen-specific CD8⁺ T cells by APCs

During infection, microbes are detected by pattern recognition receptors such as intra-cellular and extracellular TLRs and intracellular NLRs, which are expressed by APCs. Activation of these receptors initiates signaling pathways that converge at the activation of transcription factors like NF-κB and IRFs, which in turn leads to upregulation of costimulatory molecules and expression of inflammatory cytokines. Activated helper CD4⁺ T cells additionally stimulate APCs by triggering of CD40 expressed on the cell surface. Receptive CD8⁺ T cells that bind with their exclusive TCRs to MHC complexes that are loaded with microbial peptides receive in that case not only TCR signals but also costimulatory signals by ligation of CD28 (signal 2) and TNFR family members such as CD27 (and OX40 and 4-1BB) (signal 2). In addition, the released IL-12 and type I IFNs (signal 3) but also other cytokines and certain chemokines provide supplementary important signals for expansion, differentiation, and migration. Inhibitory molecules like CTLA-4 and PD-1 are upregulated and expressed on the cell surface of CD8⁺ T cells after activation and serve as inhibitory molecules to prevent immunopathology.

Fig. 2. Expansion and differentiation of naive antigen-specific CD8⁺ T cells into effector and memory cells after interaction with pathogen-activated APCs

Early clearance of antigen (but not earlier than a day) allows formation of effective memory cells. Further antigenic stimulation and inflammation leads to enhanced development of effector cells in magnitude and function. After antigen clearance, the majority of these effector CD8⁺ T cells undergo apoptosis, and the remaining forms the effector (T_EM) and central memory T-cell (T_CM) pools. If high loads of antigen persist, the responsive CD8⁺ T cells become eventually functionally exhausted. Antigen clearance of these exhausted cells compromises their maintenance severely.