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Dendritic cells (DCs) comprise distinct populations with specialized immune-regulatory functions. However, the environmental factors that determine the differentiation of these subsets remain poorly defined. Here, we report that retinoic acid (RA), a vitamin A derivative, controls the homeostasis of pre-DC (precursor of DC)-derived splenic CD11b(+)CD8α(-)Esam(high) DCs and the developmentally related CD11b(+)CD103(+) subset within the gut. Whereas mice deprived of RA signaling significantly lost both of these populations, neither pre-DC-derived CD11b(-)CD8α(+) and CD11b(-)CD103(+) nor monocyte-derived CD11b(+)CD8α(-)Esam(low) or CD11b(+)CD103(-) DC populations were deficient. In fate-tracking experiments, transfer of pre-DCs into RA-supplemented hosts resulted in near complete conversion of these cells into the CD11b(+)CD8α(-) subset, whereas transfer into vitamin A-deficient (VAD) hosts caused diversion to the CD11b(-)CD8α(+) lineage. As vitamin A is an essential nutrient, we evaluated retinoid levels in mice and humans after radiation-induced mucosal injury and found this conditioning led to an acute VAD state. Consequently, radiation led to a selective loss of both RA-dependent DC subsets and impaired class II-restricted auto and antitumor immunity that could be rescued by supplemental RA. These findings establish a critical role for RA in regulating the homeostasis of pre-DC-derived DC subsets and have implications for the management of patients with immune deficiencies resulting from malnutrition and irradiation.

Central memory CD[8.sup.+] T cells ([T.sub.cM]) and effector memory CD[8.sup.+] T cells ([T.sub.EM]) are found in humans and mice; however, their relative contributions to host immunity have only recently been examined in vivo. Further, the ability of [T.sub.CM] to treat an established tumor or infection has yet to be evaluated. To address the therapeutic potential of different tumor-reactive CD[8.sup.+] T cell memory subsets, we used an established model for the in vitro generation of [T.sub.CM] and [T.sub.EM] by using IL-15 and IL-2, respectively. Adoptively transferred [T.sub.CM] exhibited a potent in vivo recall response when combined with tumor-antigen vaccination and exogenous IL-2, leading to the eradication of large established tumors. By contrast, TEM were far less effective on a per-cell basis. Microarray analysis revealed that the signature of highly in vivo effective antitumor T cells included the overexpression of genes responsible for trafficking to secondary lymphoid tissues. This gene expression profile correctly predicted the in vitro and in vivo lymphoid-homing attributes of tumor-reactive T cells. Furthermore, we found that homing to secondary lymphoid tissue is required for optimal tumor treatment. Our findings indicated that highly in vivo effective antitumor T cells were those that initially targeted secondary lymphoid tissue, rather than tumor sites, as had previously been postulated. Thus, tumor-reactive CD[8.sup.+] T cell populations with the phenotypic and functional attributes of [T.sub.CM] may be superior to [T.sub.EM]/effector T cells for adoptive immunotherapies using concomitant tumor-antigen vaccination. IL-2 | IL-15 | | homing | immunotherapy | vaccine

Central memory CD8+ T cells (TCM) and effector memory CD8+ T cells (TEM) are found in humans and mice; however, their relative contributions to host immunity have only recently been examined in vivo. Further, the ability of TCM to treat an established tumor or infection has yet to be evaluated. To address the therapeutic potential of different tumor-reactive CD8+ T cell memory subsets, we used an established model for the in vitro generation of TCM and TEM by using IL-15 and IL-2, respectively. Adoptively transferred TCM exhibited a potent in vivo recall response when combined with tumor-antigen vaccination and exogenous IL-2, leading to the eradication of large established tumors. By contrast TEM were far less effective on a per-cell basis. Microarray analysis revealed that the signature of highly in vivo effective antitumor T cells included the overexpression of genes responsible for trafficking to secondary lymphoid tissues. This gene expression profile correctly predicted the in vitro and in viva lymphoid-homing attributes of tumor-reactive T cells. Furthermore, we found that homing to secondary lymphoid tissue is required for optimal tumor treatment. Our findings indicated that highly in vivo effective antitumor T cells were those that initially targeted secondary lymphoid tissue, rather than tumor sites, as had previously been postulated. Thus, tumor-reactive CD8+ T cell populations with the phenotypic and functional attributes of TCM may be superior to TEM/effector T cells for adoptive immunotherapies using concomitant tumor-antigen vaccination. [ABSTRACT FROM AUTHOR]

Background: Septic shock, in humans and in our well-established animal model, is associated with increases in biventricular end diastolic volume (EDV) and decreases in ejection fraction (EF). These abnormalities occur over 2 days and reverse within 10 days. Septic non-survivors do not develop an increase in EDV. The mechanism for this cardiac dysfunction and EDV differences is unknown., Methods: Purpose-bred beagles randomized to receive intrabronchial Staphylococcus aureus (n=27) or saline (n=6) were provided standard ICU care including sedation, mechanical ventilation, and fluid resuscitation to a pulmonary arterial occlusion pressure of over 10mmHg. No catecholamines were administered. Over 96h, cardiac magnetic resonance imaging, echocardiograms, and invasive hemodynamics were serially performed, and laboratory data was collected. Tissue was obtained at 66h from six septic animals., Results: From 0-96h after bacterial challenge, septic animals vs. controls had significantly increased left ventricular wall edema (6%) and wall thinning with loss of mass (15%) which was more pronounced at 48h in non-survivors than survivors. On histology, edema was located predominantly in myocytes, the interstitium, and endothelial cells. Edema was associated with significantly worse biventricular function (lower EFs), ventricular-arterial coupling, and circumferential strain. In septic animals, from 0-24h, the EDV decreased from baseline and, despite cardiac filling pressures being similar, decreased significantly more in non-survivors. From 24-48h, all septic animals had increases in biventricular chamber sizes. Survivors biventricular EDVs were significantly greater than baseline and in non-survivors, where biventricular EDVs were not different from baseline. Preload, afterload, or HR differences did not explain these differential serial changes in chamber size., Conclusion: Systolic and diastolic cardiac dysfunction during sepsis is associated with ventricular wall edema. Rather than differences in preload, afterload, or heart rate, structural alterations to the ventricular wall best account for the volume changes associated with outcome during sepsis. In non-survivors, from 0-24h, sepsis induces a more severe diastolic dysfunction, further decreasing chamber size. The loss of left ventricular mass with wall thinning in septic survivors may, in part explain, the EDV increases from 24-48h. However, these changes continued and even accelerated into the recovery phase consistent with a reparative process rather than ongoing injury., Competing Interests: DISCLOSURES The authors do not have any conflicts to disclose.

Lymph nodes (LNs) play critical roles in adaptive immunity by concentrating in one location the antigens, antigen-presenting cells, and antigen-responsive lymphocytes involved in such responses. Recent studies have revealed nonrandom localization of innate and adaptive immune cells within these organs, suggesting that microanatomical positioning optimizes responses involving sparse cooperating cells. Here, we report that the peripheral localization of LN cDC2 dendritic cells specialized for MHC-II antigen presentation is matched by a similarly biased paracortical distribution of CD4 + T cells directed by the chemoattractant receptor Ebi2. In the absence of Ebi2, CD4 + T cells lose their location bias and are delayed in antigen recognition, proliferative expansion, differentiation, direct effector activity, and provision of help for CD8 + T cell-mediated memory responses, limiting host defense and vaccine responses. These findings demonstrate evolutionary selection for distinct niches within the LN that promote cellular responses, emphasizing the critical link between fine-grained tissue organization and host defense., (Published by Elsevier Inc.)