The Role of Autophagy in iNKT Cell Development

Abstract

CD1d-restricted invariant natural killer T (iNKT) cells are innate-like T cells that express an invariant T cell receptor (TCR) α-chain and recognize self and foreign glycolipid antigens. They can rapidly respond to agonist activation and stimulate an extensive array of immune responses. Thymic development and function of iNKT cells are regulated by many different cellular processes, including autophagy, a self-degradation mechanism. In this mini review, we discuss the current understanding of how autophagy regulates iNKT cell development and effector lineage differentiation. Importantly, we propose that iNKT cell development is tightly controlled by metabolic reprogramming.

Keywords: CD1d; autophagy; invariant natural killer T cells; metabolic switch; thymic development.

Figure 1

iNKT cells undergo metabolic switching during development and differentiation to meet their changing energy demands. iNKT cells originate from CD4⁺CD8⁺ double positive (DP) thymocytes that express the invariant TCR. They are positively selected by CD1d-expressing DP thymocytes. Immature iNKT cells from DP thymocytes undergo four maturation stages characterized by differential surface expression of CD24, CD44, and NK1.1. Proliferation rate and energy demands decrease as iNKT cells progress from stages 0 and 1 to the more quiescent stages 2 and 3. This transition is accompanied by increased autophagy. Ablation of autophagy genes Atg5, Atg7, or Vps34 in iNKT cells leads to defects in the transition to a quiescent state after population expansion of thymic iNKT cells.

Figure 2

Metabolic signaling pathways that control iNKT cell development in a manner that may involve autophagy.