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Human lung fibroblasts produce CD154
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decreased the expression of CD154 mRNA and proteins in both sources of fibroblasts, whereas treatment with IL-13 increased expression levels in both. Similar expression patterns were seen in lung tissues from surgical resections, with fibrotic specimens expressing more CD154 proteins compared with normal specimens. Fibrotic regions of IPF and sarcoid lung sections stained most intensely with anti-CD154 Ab compared with normal lung. Higher levels of soluble CD154 were found in plasma and bronchoalveolar lavage fluid from IPF patients than normal controls. The authors suggest that pulmonary inflammation and wound healing are perpetuated by autocrine and paracrine activation of lung fibroblasts via the CD40-CD154 pathway. Long-term anti-tumor immunity
Cellular adoptive immunotherapy for advanced tumors employs tumor peptide-specific CD8+ T cells. However, the impact of donor effector cells on endogenous anti-tumor immune responses and tumor eradication is unknown. Dobrzanski et al. (p. 1380
) injected CD8+ type 1 or type 2 effector T cells from OVA-specific TCR transgenic OT-1 mice into syngeneic C56BL/6 mice injected 7 days earlier with B16-OVA melanoma cells that had metastasized to the lungs. Survival times among animals injected with either type of effector cell were significantly increased compared with controls (i.e., greater than 150 days vs 39 days). Survivors were resistant to rechallenge with tumor cells at 80 days after the initial challenge. Long-term survival was diminished if type 2 effector cells were deficient in either IL-4 or IL-5 and if type 1 effector cells were deficient in IFN-; perforin deficiency had no effect on either type of effector cell. Activated donor, and a small number of recipient, CD4+ and CD8+ T cells were found in lungs and spleens of recipient animals at 200 days after type 2 or type 1 effector T cell injection. Cytokine and chemokine expression in recipient-derived CD4+ and CD8+ T cells and of OVA-tetramer-positive staining CD8+ T cells were elevated in long-term survivors compared with T cells from normal control mice. Long-term tumor immunity was impaired if type 1 or type 2 effector cells were injected into IFN--/- or TNF-
-/- recipients, respectively. The authors conclude that specific cytokines derived from donor tumor-specific type 1 and type 2 effector cells influence long-term survival of tumor-bearing mice and aid in activating recipient effector cells.
B cell maturation requirements
During B cell development, Bruton’s tyrosine kinase (Btk) is required for progression of large cycling pre-B cells into small resting pre-B cells and for selection of long-lived mature B cells from immature transitional 2 (T2) cells. Middendorp and Hendriks (p. 1371
) found that bone marrow 
+ immature B cells were more affected than 
+ immature B cells by Btk deficiency. This immature phenotype was exaggerated by putting a B cell receptor transgene containing prerearranged H chain genes and a L chain gene (3–83 µ
Tg) into Btk-/- mice. Splenic B cell numbers were greatly reduced in the Btk- 3–83 µ mice, but those in Btk+ 3–83 µ mice were minimally reduced. The residual B cells in the Btk- 3–83 µ spleens were immature cells arrested at the transitional 1 stage, whereas the B cells in the Btk+ 3–83 µ spleens were at the T2 stage. Bone marrow B cells labeled in vivo with bromodeoxyuridine accumulated in the spleens of Btk+ 3–83 µ mice but were deleted within 24 h of arrival in the spleens in Btk- 3–83 µ mice. Bone marrow B cells from Btk- 3–83 µ mice crossed onto a centrally deleting MHC class I background expressed surface marker expression profiles nearly identical with wild-type mice. Transgenic expression of the apoptosis inhibitor Bcl-2 allowed splenic, but not bone marrow, Btk- 3–83 µ immature B cells to progress to the T2 stage. The data suggest that maturation of B cells in the bone marrow is dependent on Btk and on B cell receptor induction of receptor editing.
Estrogen induces dendritic cell maturation
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-estradiol (E2) on dendritic cell (DC) differentiation from bone marrow (BM) precursors in an ex vivo culture system. BM cells did not differentiate into DC when incubated for 7 days in FCS from which E2 had been removed by charcoal, whereas complete FCS did support differentiation. Addition of E2, but not dihydrotestosterone, to E2-depleted FCS on days 0, 3, and 6 restored maximal recovery of CD11c+CD11bint DC on day 7. Addition of a minimal amount of E2 with either an estrogen receptor antagonist or tamoxifen to E2-depleted BM cultures inhibited CD11c+CD11bint DC differentiation. BM from mice deficient in the subunit of the estrogen receptor had reduced DC differentiation compared with BM from wild-type mice; this reduction was reversed by addition of E2. DC that differentiated in depleted FCS to which a physiological amount of E2 had been added did not differ from DC matured in normal FCS in Ag presentation or ability to stimulate naive allogeneic CD4+ T cells. The data suggest that E2 can promote autoimmunity by directly influencing DC Ag presenting capabilities. Survival of autoreactive B cells in NZB mice
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Macrophage apoptosis
Macrophages produce the cytokine TNF- that can induce apoptosis through ligation of its receptors and subsequent activation of NF-B and Jun N-terminal kinase (JNK). Yet macrophages express TNF receptors but are resistant to the cytotoxic effects of TNF-. Liu et al. (p. 1907
) found that macrophages transfected with a superrepressor of NF-B or treated with pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-B activation, became susceptible to apoptosis when TNF- was added to the cultures. High levels of Smac/DIABLO (second mitochondria-derived activator of caspase/direct IAP binding protein with low pI), which activates caspase 3, were seen in cytosolic extracts of PDTC-treated cells to which TNF- was added but not in extracts of cells treated with PDTC only. Caspase 3 and caspase 8 inhibitors did not protect against the loss of mitochondria transmembrane potential seen in NF-B-suppressed macrophages treated with TNF-. JNK activity remained high at 24 h in macrophages treated with TNF- plus PDTC but was no longer seen at 60 min in cells treated with TNF- only. Inhibition of JNK in dual-treated cells decreased DNA fragmentation but did not prevent the loss of mitochondria transmembrane potential. The authors conclude that macrophage death involves both caspase-dependent and caspase-independent pathways and occurs through disruption of mitochondria.
OX40 and skin allograft rejection
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Summaries written by Dorothy L. Buchhagen, Ph.D.
Related articles in The JI:
and IL-13, and Implications for Fibrosis
-Induced Apoptosis of Macrophages Following Inhibition of NF-B: A Central Role for Disruption of Mitochondria
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