Programming CD8+ T cells for effective immunotherapy

Abstract

The differentiation state of CD8+ T cells has emerged as a crucial determinant of their ability to respond to tumor and infection. Signals from T-cell receptors, co-stimulatory molecules and cytokine receptors direct the differentiation process. These signals 'program' sustained and heritable gene expression patterns that govern progressive differentiation and lineage commitment. The epigenetic mechanisms by which T cells are programmed are just beginning to be elucidated. Understanding the mechanisms that control CD8+ T-cell differentiation is important in the development of novel immunotherapy strategies.

Figure 1

Progressive differentiation of adoptively transferred CD8⁺ T cells inversely correlates with in vivo anti-tumor efficacy. (a) Following adoptive transfer, naïve and early effector CD8⁺ T cells migrate to lymphoid tissues where they can interact with dendritic cells that are presenting cognate antigens. CD8⁺ T cells are programmed to proliferate, differentiate and traffic to tumor sites where they can mediate effective anti-tumor responses. After tumor clearance, T cells persist in a variety of differentiation states, providing protective immunity. (b) Intermediate effector cells are characterized by down-regulation of lymphoid homing molecules as well as having low proliferative and survival capacity. Following adoptive transfer, these cells become apoptotic or can proliferate moderately and home to tumor sites, where they can exert their cytotoxic potential. Tumor responses are sub-optimal and ultimately result in the exhaustion of T-cell responses. (c) Late effectors are characterized by poor survival and proliferative capability. After transfer, the majority of these cells undergo apoptosis. The few surviving late effectors migrate to tumor sites but are insufficient to trigger anti-tumor responses and impact on tumor growth. T cells ultimately are deleted and the tumor inexorably progresses.

Figure 2

A new hypothetical multidimensional model of CD8⁺ T-cell programming and differentiation. CD8⁺ T-cell differentiation is programmed by a variety of stimulatory and inhibitory signals from T-cell receptors (TCRs), co-stimulatory molecules and cytokine receptors. These signals induce distinct patterns of gene expression that can, through epigenetic mechanisms, be sustained and heritably transmitted. The quality of the integrated signals influences T-cell lineage commitment. Phenotypic and functional attributes are symbolized by different color hues. The strength of the integrated signals drives the T cell toward progressive senescence. T-cell differentiation through early, intermediate and late stages is represented by progressive darkening shades of cell colors. In this model, de-differentiation is not possible under physiologic conditions, although lineage commitment can be mutable. Plasticity of phenotype and function is progressively reduced as the cells approach senescence.