Resident memory T cells sound the alarm: Immunological memory protects against reinfection. Resident memory T cells (T _RM ) are long-lived and remain in the tissues where they first encountered a pathogen (see the Perspective by Carbone and Gebhardt). Schenkel et al. and Ariotti et al. found that CD8 ⁺ T _RM cells act like first responders in the female reproductive tissue or the skin of mice upon antigen reencounter. By secreting inflammatory proteins, T _RM cells rapidly activated local immune cells to respond, so much so that they protected against infection with an unrelated pathogen. Iijima and Iwasaki found that CD4 ⁺ T _RM cells protected mice against reinfection with intravaginal herpes simplex virus 2. Science , this issue p. 98 , p. 101 , p. 93 ; see also p. 40

Dynamic Protection: During an immune response, CD8 ⁺ T cells are recruited to provide protection. Most cells differentiate into short-lived effectors that help to clear the pathogen, whereas others form long-lived memory cells to protect against reinfection. Gerlach et al. (p. 635 , published online 14 March) and Buchholz et al. (p. 630 , published online 14 March) used in vivo fate mapping of mouse T cells with a defined specificity during a bacterial infection to show that the dynamics of the single-cell response are not uniform. The response of a particular T cell population is the average of a small number of clones that expand greatly (“large clones”) and many clones that only proliferate at low amounts (“small clones”). The memory pool arises largely from small clones whereas effectors are primarily made up of large clones.

Histone deacetylases (HDACs) counterbalance acetylation of lysine residues, a protein modification involved in numerous biological processes. Here, Hdac1 and Hdac2 conditional knock‐out alleles were used to study the function of class I Hdac1 and Hdac2 in cell cycle progression and haematopoietic differentiation. Combined deletion of Hdac1 and Hdac2, or inactivation of their deacetylase activity in primary or oncogenic‐transformed fibroblasts, results in a senescence‐like G1 cell cycle arrest, accompanied by up‐regulation of the cyclin‐dependent kinase inhibitor p21Cip. Notably, concomitant genetic inactivation of p53 or p21Cip indicates that Hdac1 and Hdac2 regulate p53–p21Cip‐independent pathways critical for maintaining cell cycle progression. In vivo , we show that Hdac1 and Hdac2 are not essential for liver homeostasis. In contrast, total levels of Hdac1 and Hdac2 in the haematopoietic system are critical for erythrocyte‐megakaryocyte differentiation. Dual inactivation of Hdac1 and Hdac2 results in apoptosis of megakaryocytes and thrombocytopenia. Together, these data indicate that Hdac1 and Hdac2 have overlapping functions in cell cycle regulation and haematopoiesis. In addition, this work provides insights into mechanism‐based toxicities observed in patients treated with HDAC inhibitors.

Somatic hypermutation of Ig genes enables B cells of the germinal center to generate high-affinity immunoglobulin variants. Key intermediates in somatic hypermutation are deoxyuridine lesions, introduced by activation-induced cytidine deaminase. These lesions can be processed further to abasic sites by uracil DNA glycosylase. Mutagenic replication of deoxyuridine, or of its abasic derivative, by translesion synthesis polymerases is hypothesized to underlie somatic hypermutation. Rev1 is a translesion synthesis polymerase that in vitro incorporates uniquely deoxycytidine opposite deoxyuridine and abasic residues. To investigate a role of Rev1 in mammalian somatic hypermutation we have generated mice deficient for Rev1. Although Rev1^−/− mice display transient growth retardation, proliferation of Rev1^−/− LPS-stimulated B cells is indistinguishable from wild-type cells. In mutated Ig genes from Rev1^−/− mice, C to G transversions were virtually absent in the nontranscribed (coding) strand and reduced in the transcribed strand. This defect is associated with an increase of A to T, C to A, and T to C substitutions. These results indicate that Rev1 incorporates deoxycytidine residues, most likely opposite abasic nucleotides, during somatic hypermutation. In addition, loss of Rev1 causes compensatory increase in mutagenesis by other translesion synthesis polymerases.

CD4⁺Foxp3⁺ regulatory T cells (T_reg cells) are largely autoreactive yet escape clonal deletion in the thymus. We demonstrate here that CD27–CD70 co-stimulation in the thymus rescues developing T_reg cells from apoptosis and thereby promotes T_reg cell generation. Genetic ablation of CD27 or its ligand CD70 reduced T_reg cell numbers in the thymus and peripheral lymphoid organs, whereas it did not alter conventional CD4⁺Foxp3⁻ T cell numbers. The CD27–CD70 pathway was not required for pre-T_reg cell generation, Foxp3 induction, or mature T_reg cell function. Rather, CD27 signaling enhanced positive selection of T_reg cells within the thymus in a cell-intrinsic manner. CD27 signals promoted the survival of thymic T_reg cells by inhibiting the mitochondrial apoptosis pathway. CD70 was expressed on Aire⁻ and Aire⁺ medullary thymic epithelial cells (mTECs) and on dendritic cells (DCs) in the thymic medulla. CD70 on both mTECs and DCs contributed to T_reg cell development as shown in BM chimera experiments with CD70-deficient mice. In vitro experiments indicated that CD70 on the CD8α⁺ subset of thymic DCs promoted T_reg cell development. Our data suggest that mTECs and DCs form dedicated niches in the thymic medulla, in which CD27–CD70 co-stimulation rescues developing T_reg cells from apoptosis, subsequent to Foxp3 induction by TCR and CD28 signals.