Summary Polarized segregation of proteins in T cells is thought to play a role in diverse cellular functions including signal transduction, migration, and directed secretion of cytokines. Persistence of this polarization can result in asymmetric segregation of fate-determining proteins during cell division, which may enable a T cell to generate diverse progeny. Here, we provide evidence that a lineage-determining transcription factor, T-bet, underwent asymmetric organization in activated T cells preparing to divide and that it was unequally partitioned into the two daughter cells. This unequal acquisition of T-bet appeared to result from its asymmetric destruction during mitosis by virtue of concomitant asymmetric segregation of the proteasome. These results suggest a mechanism by which a cell may unequally localize cellular activities during division, thereby imparting disparity in the abundance of cell fate regulators in the daughter cells.

IntroductionPathogen clearance requires that CD8 ϩ effector T cells produce inflammatory cytokines and develop cytolytic activity against infected target cells, after which a small number of memory cells survive that rapidly regain effector function in the event of rechallenge. During this process, a relatively homogeneous pool of naive CD8 ϩ T cells differentiates into heterogeneous pools of effector and memory CD8 ϩ T cells. 1 To initiate this differentiation program, naive T cells integrate signals from peptide:major histocompatibility complex (MHC) complexes, costimulatory molecules and cytokines. Manipulation of these signals influences the quality and kinetics of CD8 ϩ T-cell memory differentiation. [1][2][3][4] The molecular signals that orchestrate the function and diversification of effector and memory CD8 ϩ T-cell subsets downstream of these receptors are beginning to be elucidated and how T-cell receptor (TCR) signals affect CD8 ϩ T-cell effector function and fate choices is not fully understood. [5][6][7][8][9][10][11][12][13][14] The CD8 ϩ effector T-cell pool can be divided into terminally differentiated, short-lived KLRG-1 hi IL-7r␣ lo effector cells (SLECs) and less differentiated KLRG-1 lo IL-7r␣ hi memory precursor cells (MPECs). 3,[15][16][17] SLECs typically produce the effector cytokine interferon␥ (IFN␥) and may also coproduce tumor necrosis factor␣ (TNF␣) in response to antigen but only memory precursors can produce interleukin-2 (IL-2) in addition to IFN␥ and TNF␣. 17,18 The memory pool is a heterogeneous population that is commonly divided into effector memory (Tem) and central memory (Tcm) defined by surface markers including CD62L, which is expressed at higher levels on Tcm. 19,20 After contraction, the ratio of CD62L hi to CD62L lo memory cells increases, although the number of memory cells in the blood and spleen remains constant. While it is not clear whether this transition is the result of direct conversion of Tem to Tcm cells or preferential outgrowth of Tcm cells, it is clear that the rate of transition can be influenced by the strength and duration of initial antigenic stimulus. 1,8,21 Furthermore, the memory pool undergoes functional maturation, gaining enhanced proliferative capabilities. 22,23 The relative frequencies of memory subsets can vary depending on the nature or persistence of the inciting antigen and understanding how these factors influence memory development and maturation is important for predicting the quality of secondary responses. [24][25][26][27] While multiple cytokines and transcription factors are known to affect the balance between terminal differentiation and memory formation, the role of TCR signals has been more difficult to ascertain. 3,6,7,11,16,28,29 Adjustments in the quantity, quality, or duration of antigen presentation affect the magnitude of the primary response and the kinetics of differentiation, but do not appear to affect the functional quality of the cells. 3,5,12,14,21,28,[30][31][32][33] However, specific TCR signals can differential...