SUMMARY T cell receptor (TCR) signaling without CD28 can elicit primary effector T cells, but memory T cells generated during this process are anergic, failing to respond to secondary antigen exposure. We show that upon T cell activation, CD28 transiently promotes expression of carnitine palmitoyltransferase 1a (Cpt1a), an enzyme that facilitates mitochondrial FAO, before the first cell division, coinciding with mitochondrial elongation and enhanced spare respiratory capacity (SRC). microRNA-33 (miR33), a target of thioredoxin-interacting protein (TXNIP), attenuates Cpt1a expression in the absence of CD28, resulting in cells that thereafter are metabolically compromised during reactivation or periods of increased bioenergetic demand. Early CD28-dependent mitochondrial engagement is needed for T cells to remodel cristae, develop SRC, and rapidly produce cytokines upon restimulation – cardinal features of protective memory T cells. Our data show that initial CD28 signals during T cell activation prime mitochondria with latent metabolic capacity essential for future T cell responses.

Summary The IRE1/XBP1 signaling pathway is part of a cellular program that protects from endoplasmic reticulum (ER) stress, but also controls development and survival of immune cells. Loss of XBP1 in splenic type 1 conventional dendritic cells (cDC1s) results in phenotypic and functional alterations without affecting cell survival. However, in mucosal cDC1s, loss of XBP1 impaired survival in a tissue specific manner - while lung cDC1s die, intestinal cDC1s survive. This was not caused by differential activation of ER stress cell death regulators CHOP or JNK. Rather, cell fate was determined by a differential ability to shut down protein synthesis via a protective ATF4-dependent integrated stress response. In addition, regulated IRE1 dependent mRNA decay (RIDD) occurred mainly in intestinal cDC1s, and compound deficiency of IRE1 endonuclease led to cDC1 loss also in the intestine. Thus, mucosal DCs differentially mount ATF4 and IRE1 dependent adaptive mechanisms to survive in the face of ER stress.