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Aire-Independent Central Tolerance
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R mAb but returned to background by 24 h. Immunofluorescence localized CII protein in epithelial cells of the thymic medulla of wild-type and Aire–/–, but not lta–/–, mice; CII and aire proteins did not colocalize. Both lta–/– and ltbr–/– mice spontaneously developed high titers of anti-CII Ab, as did Rag1–/– recipients of ltbr–/– splenocytes or ltbr–/– splenic T cells plus wild-type B cells. Thymectomized B6 recipients of ltbr–/– thymi depleted of bone marrow-derived cells plus wild-type bone marrow also developed higher anti-CII Ab levels than controls. Mild symptoms of arthritis developed in wild-type B6 mice, but rapid collagen-induced arthritis appeared in lta–/– mice only after immunization with CII in CFA. CD4+ T cells from CII-immunized lta–/–, but not wild-type, mice responded vigorously to CII Ag in in vitro proliferation assays. The experiments demonstrate that collagen-induced arthritis induction is controlled by central tolerance through ectopic expression of CII in mTECs mediated by LT, not aire, in this mouse model of rheumatoid arthritis. Defining Hemopoietic Stem Cells
Hemopoietic stem cells (HSCs) are self-renewing and differentiate into all blood cell lineages. However, there are few details regarding their cell cycle kinetics. Nygren et al. (p. 201 ) found that 100% of 14.5-day fetal liver HSCs had proliferated within 48 h. BrdU incorporation showed that more than half of HSCs were in G1, compared with less than one-fourth of fetal liver hemopoietic progenitor cells (HPCs). Additionally, 14% of HSCs but no HPCs were in G0. A slower turnover rate of HSCs compared with HPCs was confirmed by a time course study of in vivo BrdU incorporation that showed cell cycle transit times in fetal liver of 10.6 and 5.6 h, respectively. Isolated G0-G1 fractions were enriched over S-G2-M fractions for multilineage long-term HSC (LT-HSC) repopulating activity when transplanted in lethally irradiated congenic adult recipients. The G1 population from a primary or secondary ex vivo expansion of HSCs was highly enriched in LT-HSC repopulating activity; repopulating activity of the S-G2-M population was due to contaminating short-term HSCs and LT-HSCs. HSCs that incorporated a high level of a label during division ex vivo (slowly dividing cells), but not HSCs that incorporated a low level of the label (rapidly dividing), had LT-HSC reconstitution potential after transfer into lethally irradiated recipients. The data indicate that proliferating LT-HSCs accumulate in G1. Their prolonged transit through G0-G1 defines hemopoietic stem cells and may be a requirement for self-renewal.
Central Tolerance in Type 1 Diabetes
Proinsulin-2 expression is known to lower susceptibility to type 1 diabetes in humans and mice. Although expression of preproinsulin (proins-2) in medullary thymic epithelial cells in mice suggests central tolerance, lack of peripheral tolerance has not been established. Faideau et al. (p. 53
) demonstrated proliferation and IFN-
production by proins-2–/– CD4+ T cells after proins-2 stimulation in vitro; wild-type cells were nonreactive regardless of parental origin of the proin-2 gene. CD4+ T cells from irradiated proins-2–/–, but not wild-type, mice made chimeric with wild-type or proins-2–/– bone marrow produced IFN- in response to proins-2 in vitro. Cells from wild-type or proins-2–/– bone marrow chimeras with an engrafted proins-2–/– thymus in a thymectomized wild-type host also produced IFN- upon stimulation in vitro, although no islet infiltration or insulin Abs were detected in vivo. CD4+ T cells from CD3
-immunodeficient mice expressing proins-2 in their islets did not demonstrate in vitro Ag reactivity 2 mo after adoptive transfer with proins-2–/– CD4+ T cells unless the mice were immunized with proin-2 at 2 mo. However, wild-type recipients of unprimed proins-2–/– cells developed Ag-reactive cells after in vivo immunization with the Ag, as did chimeras doubly engrafted with wild-type plus proins-2–/– thymii that received unprimed T cell-depleted wild-type bone marrow. The authors use bone marrow and thymus chimeras to show that central tolerance to proins-2 is conferred by expression of a single proins-2 allele in thymic epithelium.
Tumor Escape Mutants
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. Forty percent of mice immunized with eye-derived tumor cells were protected against tumor development after challenge with wild-type tumor cells, but 60% were protected after challenge with eye-derived tumor cells. The authors show that an immune escape phenotype rapidly develops in tumor cells in the anterior chamber of the mouse eye in the absence of selective T cell pressure and suggest that it is due to epigenetic, not genetic, changes induced by the ocular environment. Resisting P. aeruginosa keratitis
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, IL-1R, TLR4, IL-18, IFN-, and MIP-2 mRNA levels than controls. IL-1R1, TLR4, proinflammatory cytokine, and type-1 immune response-associated cytokine mRNA levels were reduced in LPS- or influenza virus protein-stimulated BALB/c monocytes/macrophage cells transfected with a plasmid expressing SIGIRR. IL-1-mediated NF-
B activation was reduced by cotransfection of the SIGIRR-expressing plasmid plus IL-1R1 into mouse cells carrying an NF-B reporter plasmid. LPS-induced NF-B activation similarly was inhibited by transfection of the SIGIRR-expressing plasmid into cells carrying a TLR4 signaling complex. The data indicate that the role of SIGIRR in resisting P. aeruginosa infection of corneas in BALB/c mice involves negative regulation of type-1 responses and IL-1R1 and TLR4 signaling. Treg Homeostasis Indexed to IL-2
Maintenance of absolute numbers and relative sizes of populations of immune cells is necessary to prevent deregulation and disease. The Freitas laboratory showed that CD4+CD25+ regulatory T cells (Tregs) control peripheral CD4+ T cell homeostasis and implicated IL-2 and its receptor. In a continuation of their work, Almeida et al. (p. 192
) transferred varying proportions of Treg and naive T cells into T cell-deficient hosts; similar numbers of Treg cells were recovered from recipients 8–10 wk later. A constant fraction (10%) of Treg cells was obtained from irradiated Rag2–/– mice transferred with varying mixtures of bone marrow from wild-type and CD25–/– mice; CD25+ bone marrow cells able to use IL-2 expanded preferentially in the peripheral CD4+ T cell pool. IL-2–/– mice injected with mixed bone marrow from CD25–/– and IL-2–/– donors, but not with bone marrow from IL-2–/– donors alone, generated Tregs expressing foxp3 mRNA at levels similar to wild-type Tregs. Experiments using varying mixtures of bone marrow in Rag2–/–IL-2–/– recipients showed that only mice receiving an 
T cell source of IL-2 (CD25–/– bone marrow) developed Treg cells and were protected against death from autoimmune inflammatory bowel disease. IL-2–/– Tregs expanded significantly in Rag2–/–IL-2–/– hosts when cotransferred with IL-2+CD4+ T cells but not when transferred alone or with IL-2–/–CD4+ T cells; the fraction and number of wild-type Tregs were higher when cotransferred with naïve IL-2+ vs IL-2–/– T cells. Cotransfer of Tregs prevented inflammatory bowel disease in Rag2–/– hosts transferred with naïve CD4+ T cells alone. The data show that peripheral expansion and survival of Tregs in mice is indexed to the number of CD4+ T cells producing IL-2.
Preventing HIV-1-Induced Neurotoxicity
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, as measured by ELISA, and activated p38 MAPK and JNK; MLK3 inhibitors prevented the cytokine release and kinase activations. However, only p38 MAPK, but not JNK, inhibitors abrogated Tat- or gp120-induced TNF- production by monocytes. The data confirm that MLK3 is involved in HIV-1-associated dementia and that MLK3 inhibitors prevent HIV-1 Tat- or gp120-induced apoptosis of primary rat neurons and human monocytes. Tat or gp120 induces phosphorylation of both p38 MAPK and JNK in neurons, but of only p38 MAPK in monocytes. Summaries written by Dorothy L. Buchhagen, Ph.D.
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