After antigen encounter, naive lymphocytes differentiate into populations of memory cells that share a common set of functions including faster response to antigen re-exposure and the ability to self-renew. However memory lymphocytes in different lymphocyte lineages are functionally and phenotypically diverse. It is not known whether discrete populations of T and B cells use similar transcriptional programs during differentiation into the memory state. We used cross-species genomic analysis to examine the pattern of genes upregulated during the differentiation of naive lymphocytes into memory cells in multiple populations of human CD4, CD8 and B cell lymphocytes as well as two mouse models of memory development. We identified and validated a signature of genes that was upregulated in memory cells compared to naive cells in both human and mouse CD8 memory differentiation, suggesting marked evolutionary conservation of this transcriptional program. Surprisingly, this conserved CD8 differentiation signature was also upregulated during memory differentiation in CD4 and B cell lineages. To validate the biologic significance of this signature we showed that alterations in this signature of genes could distinguish between functional and exhausted CD8 T cells from a mouse model of chronic viral infection. Finally, we generated genome-wide microarray data from tetramer-sorted human T cells and showed profound differences in this differentiation signature between T cells specific for HIV from those specific for influenza. Thus, our data suggest that in addition to lineage-specific differentiation programs, T and B lymphocytes employ a common transcriptional program during memory development that is disrupted in chronic viral infection.

Despite profound T-cell immunodeficiency, most patients treated with chemotherapy do not succumb to infection. The basis for residual protective immunity in lymphopenic patients is not known. We prospectively measured Tcell numbers, thymopoiesis, and T-cell memory in 73 children undergoing a 2-year chemotherapy regimen for acute lymphoblastic leukemia (ALL) and compared them to an age-matched cohort of 805 healthy children. Most patients had profound defects in CD4 and CD8 T-cell numbers at diagnosis that did not recover during the 2 years of therapy. Thymic output and the fraction of naive T cells were significantly lower than in healthy controls. However, the remaining T-cell compartment was enriched for antigen-experienced, memory T cells defined both by phenotype and by function. This relative sparing of T-cell memory may, in part, account for the maintenance of protective immunity in lymphopenic patients treated for ALL. Moreover, because the memory T-cell compartment is least affected by ALL and its treatment, strategies to induce immunity to pathogens or tumor antigens in cancer patients may be most successful if they seek to expand preexisting memory T cells. IntroductionPatients undergoing chemotherapy for cancer are susceptible to infection, particularly in hematologic malignancies such as acute lymphoblastic leukemia (ALL) where infections account for 80% of remission deaths. [1][2][3] However, while infection represents a significant complication of chemotherapy, the number of patients who succumb to infection is low. For instance, fewer than 1% of children undergoing maintenance therapy for ALL die from infection. 3 Although infection prophylaxis and good supportive care are likely to contribute to this low infectious mortality, the majority of patients with ALL appear to retain protective immunity against infection despite prolonged chemotherapy. The nature of this residual immune function in lymphopenic patients is not known.In the normal host the peripheral T-cell compartment consists of naive T cells, which originate in the thymus, and memory T cells, which have differentiated from naive T cells in response to antigen exposure. Memory T cells can rapidly proliferate and acquire effector function on re-exposure to antigen. Together with antibody response, memory T cells are central to the maintenance of protective immunity. However, the fate of the memory T-cell compartment in patients treated with chemotherapy is poorly understood. Seminal studies by Mackall et al 4-7 described the profound depletion seen in the T-cell compartment following chemotherapy. They showed that intensive chemotherapy is associated with a near-total loss of naive CD4 T cells, which do not reappear until several months after the end of treatment. [4][5][6][7] Recent data using assays that quantify thymic output have also shown a marked decrease in thymic output in patients treated with chemotherapy and radiation, suggesting that direct thymic injury may account for this lack of naive T cells. 8,9 Together, these studies...

Acute pain medicine (APM) has been incorporated into healthcare systems in varied manners with some practices implementing a stand-alone acute pain service (APS) staffed by consultants who are not simultaneously providing care in the operating room (OR). In contrast, other practices have developed a concurrent OR-APS model where there is no independent team beyond the intraoperative care providers. There are theoretical advantages of each approach primarily with respect to patient outcomes and financial cost, and there is little evidence to instruct best practice. In this daring discourse, we present two opposing perspectives on whether or not APM should be a stand-alone service. While evidence to guide best practice is limited, our goal is to encourage discussion of the varied APS practice models and research into their impact on outcomes and costs.