The transcription factor T-bet is critical for cytotoxic T lymphocyte (CTL)

The transcription factor T-bet is critical for cytotoxic T lymphocyte (CTL) differentiation but it is unclear how it operates in a graded manner in the formation of both terminal effector and memory precursor cells during viral infection. were bound by T-bet and this binding was altered by ZEB2 deficiency. Furthermore T-bet overexpression could not fully bypass ZEB2 function. Thus the coordinated actions of T-bet and ZEB2 outline a novel genetic pathway that causes commitment of CTLs to terminal differentiation thereby restricting their memory cell potential. CD8+ T cells are a crucial component of cell-mediated immunity against intracellular pathogens AMG-073 HCl (Cinacalcet HCl) such as viruses and can provide long-term protection from reinfection for decades after the initial contamination is usually cleared (Ahmed and Gray 1996 Jameson and Masopust 2009 Despite the importance of cytotoxic T lymphocyte (CTL) immunity in controlling viral infections a successful T cell-based vaccine has yet to be developed. Many intracellular pathogens for which we still lack effective vaccines such as HIV involve pathogens that can escape neutralizing antibody; a T cell-based vaccine strategy may improve protection from such pathogens. Harnessing this potential requires greater immunological insight into how T cell memory forms after contamination and vaccination. Our understanding of effector and memory T cell development has advanced considerably over the past decade. In response to acute infections CD8+ T cells expand into a heterogeneous populace of effector cells that can be phenotypically functionally and anatomically distinguished. Importantly the long-term fates of the effector cells also differ after contamination in that the majority of cells (～90-95%) pass away and a minority persist to give rise to longer-lived memory T cells (Ahmed and Gray JARID1C 1996 Jameson and Masopust 2009 Kaech and Cui 2012 Often increased IL-7 receptor α (IL-7R) expression on effector cells identifies those with a higher potential to persist and seed diverse populations of central memory (TCM) effector memory (TEM) and resident memory (TRM) T cells (Sallusto et al. 1999 Schluns et al. 2000 Kaech et al. 2003 Huster et al. 2004 Joshi et al. 2007 Jameson and Masopust 2009 Kaech and Cui 2012 Mackay et al. 2013 These antigen-specific IL-7R+ CD8+ T cells generally referred to as memory precursor (MP) cells are endowed with longevity and the AMG-073 HCl (Cinacalcet HCl) ability to self-renew and regenerate new clonal bursts of effector cells (i.e. they are multipotent). Conversely terminally differentiated effector (TE) cells often recognized by killer-cell lectin-like receptor G1 (KLRG1) expression are potent killers and IFN-γ secretors that have decreased longevity proliferative potential and restricted plasticity (Voehringer et al. 2001 Thimme et al. 2005 Joshi et al. 2007 2011 Olson et al. 2013 This divergence in long-term fates raises the questions: How is the process AMG-073 HCl (Cinacalcet HCl) of terminal differentiation programmed and how is usually plasticity managed in CTLs as they differentiate during contamination? Gene expression profiling experiments have identified unique transcriptional signatures for MP cells (KLRG1lo IL7-Rhi) and TE cells (KLRG1hi IL7Rlo; Joshi et al. 2007 Rutishauser et al. 2009 Best et al. 2013 Arsenio et al. 2014 Further T-bet (encoded by promote development of memory CD8+ T cells and their progenitors (Ichii et al. 2002 2004 Jeannet et al. 2010 Zhou et al. 2010 Cui et al. 2011 Yang et al. 2011 Hess Michelini et al. 2013 Kim et al. 2013 Tejera et al. 2013 However little is known about how these transcription factors interact or impact each other’s expression or function to develop unique subsets of CTLs with diverse cell fates. Small differences in the amounts of some of these transcriptional regulators can have profound effects on CTL fate. For example T-bet operates in a graded manner in effector CTLs with moderate levels permitting memory cell fates but relatively higher levels promoting terminal differentiation (Joshi et al. 2007 Mechanistically how modest differences in T-bet expression translate into unique changes in gene expression function and specification of long-term fates in CTLs is not clear. This study identifies AMG-073 HCl (Cinacalcet HCl) a novel role for the transcription factor ZEB2 as one such translator of.