SUMMARY In an immune response, CD4+ T cells expand into effector T cells and then contract to survive as long-lived memory cells. To identify age-associated defects in memory cell formation, we profiled activated CD4+ T cells and found an increased induction of the ATPase CD39 with age. CD39+ CD4+ T cells resembled effector T cells with signs of metabolic stress and high susceptibility to undergo apoptosis. Pharmacological inhibition of ATPase activity dampened effector cell differentiation and improved survival, suggesting that CD39 activity influences T cell fate. Individuals carrying a low-expressing CD39 variant responded better to vaccination with an increase in vaccine-specific memory T cells. Increased inducibility of CD39 after activation may contribute to the impaired vaccine response with age.

Adaptive immune responses in humans rely on somatic genetic rearrangements of Ig and T-cell receptor loci to generate diverse antigen receptors. It is unclear to what extent an individual's genetic background affects the characteristics of the antibody repertoire used in responding to vaccination or infection. We studied the B-cell repertoires and clonal expansions in response to attenuated varicellazoster vaccination in four pairs of adult identical twins and found that the global antibody repertoires of twin pair members showed high similarity in antibody heavy chain V, D, and J gene segment use, and in the length and features of the complementarity-determining region 3, a major determinant of antigen binding. These twin similarities were most pronounced in the IgM-expressing B-cell pools, but were seen to a lesser extent in IgG-expressing B cells. In addition, the degree of antibody somatic mutation accumulated in the B-cell repertoire was highly correlated within twin pair members. Twin pair members had greater numbers of shared convergent antibody sequences, including mutated sequences, suggesting similarity among memory B-cell clonal lineages. Despite these similarities in the memory repertoire, the B-cell clones used in acute responses to ZOSTAVAX vaccination were largely unique to each individual. Taken together, these results suggest that the overall Bcell repertoire is significantly shaped by the underlying germ-line genome, but that stochastic or individual-specific effects dominate the selection of clones in response to an acute antigenic stimulus.H uman responses to infectious diseases or vaccinations rely on many different cell populations, soluble mediators, and interactions between cells. Prior studies of identical twins have highlighted aspects of human immunity that are heavily influenced by the germ-line genome, such as the proportions of particular leukocyte subsets (1). In addition to the germ line-encoded genes that affect the responses of immune cells, mammalian immune systems also make use of somatic genetic rearrangements to produce diverse repertoires of immunoglobulins (Igs) and T-cell receptors (TCRs) for specific recognition of foreign antigens. Antibody and TCR sequences are generated through the combinatorial use of a set of predetermined gene segments in the genome, as well as by more random exonuclease digestion of the ends of the gene segments, and addition of nontemplated bases at the junctions between gene segments. Clonal expansion of the populations of cells that recognize particular pathogens provides immune system memory of prior exposures.The germ-line genome sequence plays a role in the initial generation and selection of antibody and T-cell receptor repertoires in each individual, as demonstrated in prior work (2-6). Whether such genetic effects have a prominent effect on the clonal B-cell responses to particular pathogens or vaccinations is much less clear. In adult humans, it is possible that the accumulation of the effects of responses to prior antigenic exposures in...

IntroductionThe tyrosine kinase Itk, a member of the Tec family of nonreceptor tyrosine kinases, is expressed in T cells and regulates signaling via the T-cell receptor. 1 On T-cell receptor activation, Itk phosphorylates and activates phospholipase-␥1, leading to calcium influx, as well as activation of nuclear factor-B, nuclear factor of activated T cell, and Ras-dependent signaling pathways. Signals regulated by Itk control the development of ␣␤ T cells such that positive and negative selection is affected in the absence of Itk. In addition, Itk also controls the development of populations of T cells that have a naive phenotype (CD62L hi /CD44 lo ), such that, in its absence, nonconventional CD4 ϩ and CD8 ϩ T cells carrying a memory phenotype (CD62L lo /CD44 hi ) and exhibiting innate function predominate. [2][3][4][5] Itk signals also regulate the development of Th2 cells such that, in its absence, T cells from Itk null mice have defects in the production of Th2 cytokines, and these mice have defects in generating Th2 response in several infection and allergic asthma models. [6][7][8][9] Despite this defect in the generation of effective Th2 responses and secretion of Th2 cytokines, Itk null mice paradoxically exhibit increased class switch in B cells to IgE and elevated levels of serum IgE. 10,11 What is not clear is the source of cytokines that could drive the increase in class switch to IgE.T cells are divided into ␣␤ T cells and ␥␦ T cells according to their TCR expression. Both ␣␤ and ␥␦ T cells arise from the most immature CD4 Ϫ CD8 Ϫ double-negative (DN) thymocytes in the thymus. DN thymocytes are divided into 4 developmental stages according to the surface expression of CD25 and CD44, from most immature DN1 to more mature DN4 cells. ␥␦ T cells separate from ␣␤ T cells at DN stages, although the exact time point and the mechanisms involved in this process are still elusive. 12,13 Several studies have shown that the strength of the TCR signal is important for T-cell lineage commitment. Stronger TCR signals favor the development of ␥␦ T cells, whereas the weaker signals favor the development of ␣␤ T cells. 14-16 Studies on ␥␦ TCR transgenic mice have demonstrated that negative selection occurs during the development of ␥␦ T cells in adult thymus, but whether positive selection is necessary is still controversial.␥␦ T cells can produce Th1, Th2, and Th17 cytokines thus having multiple functions in the modulating immune responses, such as host defense and tumor immunity. [17][18][19][20][21][22][23] Both murine and human ␥␦ T cells have been suggested to provide help to B cells, which is correlated with their production of the Th2 cytokine interleukin-4 (IL-4). [24][25][26] More interestingly, several studies showed that only the CD4 ϩ ␥␦ T cells are able to produce 21 We show here that mice lacking Itk have altered ␥␦ T-cell development such that they have more of these cells. We also show that the CD4 ϩ population of ␥␦ T cells is expanded in the absence of Itk and that this population can induce B cell...

Nonresonant x-ray Raman scattering ͑XRS͒ is the inelastic scattering of hard x rays from the K shell of low-Z elements or the less tightly bound shells of heavier elements. In the limit of low momentum transfer q, XRS is determined by the same transition matrix element as is measured by x-ray absorption spectroscopies. However, XRS at higher q can often access higher order multipole transitions which help separate the symmetry of various contributions to the local density of states. The main drawback of XRS is its low cross section-a problem that is compounded for a q-dependent study. To address this issue, we have constructed a multielement spectrometer to simultaneously measure XRS at ten different values of q. By means of example, we report new measurements of the XRS from the L-and K-edges of Mg. This instrument is now available to general users at the Advanced Photon Source as the lower energy resolution inelastic x-ray scattering ͑LERIX͒ spectrometer.