The Journal of Immunology, 2008,
180,
681
-682
Copyright © 2008 by The American Association of Immunologists, Inc.
IN THIS ISSUE
Ag-Specific Arthritis
Autoimmune arthritis develops in multiple human autoimmune diseases, but the functional role of CD4+ T cells in arthritis is not fully understood. To address this issue, Rankin et al. (p. 833
) developed a novel transgenic mouse model of inflammatory arthritis that expressed a CD4+ TCR specific for a hemagglutinin (HA) Ag and co-expressed HA under the control of an MHC II promoter. The majority of these TS1xHACII mice spontaneously developed inflammatory arthritis in adulthood. Although systemic B cell activation was observed in these mice, TS1xHACII.JH–/– mice, which lack B cells, still developed arthritis, indicating that disease development did not require B cells or autoantibodies. In addition, arthritis developed in TS1xHACII.RAG–/– mice, indicating that CD4+ T cells recognizing a single self-peptide were sufficient for disease induction. Although many TCR-transgenic T cells underwent negative selection in the thymus, cells expressing low levels of the transgenic TCR escaped selection, expanded, and spontaneously produced inflammatory cytokines in the periphery. These Ag-specific activated T cells also specifically accumulated in lymph nodes draining major joints. This study demonstrates that inflammatory arthritis can develop without the participation of autoantibodies and introduces a useful mouse model for studies of autoreactive CD4+ T cells in this disease.
Cytokine Regulation of Asthma
Eosinophils are known to play a pivotal role in allergic asthma, but inhibition of IL-5 has had only limited effectiveness in the treatment of both murine and human allergic inflammation. Asquith et al. (p. 1199
) hypothesized that the IL-5-independent functions of eosinophils in asthma could require signaling through the common β-chain (βc) shared by the receptors for IL-5, IL-3, and GM-CSF. Indeed, ablation of βc prevented eosinophil expansion and accumulation in the blood and lungs of allergen-sensitized mice. These βc–/– mice also demonstrated greatly reduced features of both the early and late phases of the asthmatic response as measured by IgE production and airway hyperreactivity, respectively. Examination of T cell responses in the lungs and peribronchial lymph nodes of allergen-sensitized βc–/– mice revealed severe defects in CD4+ T cell activation and migration, particularly in Th2 cell proliferation and cytokine production. Expansion and maturation of pulmonary myeloid dendritic cells were also defective in the absence of βc signaling. Taken together, these data define a role for βc in allergic inflammation and identify this receptor chain as a potentially useful therapeutic target for asthma.
Hormones and DCs
Dendritic cell (DC) differentiation can be mediated by either GM-CSF or Flt3 ligand (FL) both in vitro and in vivo, with GM-CSF predominating in inflammatory conditions and FL in homeostasis. How these pathways are affected by female sex hormones is a clinically significant question, as females are known to be more susceptible than males to many autoimmune diseases. Carreras et al. (p. 727
) found that 17-β-estradiol (E2) had opposing effects on GM-CSF- vs FL-mediated DC differentiation. In vitro, physiological levels of E2 enhanced DC differentiation induced by GM-CSF, whereas the same concentrations of E2 profoundly decreased cell viability and altered the ratio of DC subsets in FL-stimulated cultures. Studies with estrogen receptor (ER)-deficient mice indicated that the effects of E2 on both pathways of DC differentiation were mediated through the same receptor, ER
. E2 was also found to act on the same subsets of myeloid progenitor cells to exert both sets of effects. In cultures of progenitor cells incubated with both FL and GM-CSF, E2 promoted DC differentiation as in GM-CSF cultures but decreased overall cell viability as in FL cultures. These data address the differential susceptibility of females to disease by demonstrating a hormonal influence on DCs in inflammatory vs homeostatic conditions.
Adoptive Transfer: A Warning
Adoptive transfer of TCR-transgenic CD4+ T cells has been used extensively to study the behavior of Ag-specific cells during an immune response. Upon transfer into wild-type hosts, these cells proliferate and then rapidly decline through what has been assumed to be a normal contraction response that selects against clonal dominance and establishes Ag-specific memory. However, Duffy et al. (p. 747
) found that these presumably syngeneic transgenic T cells were actively targeted by host NK and CD8+ T cells. The authors transferred naive DO11.10 TCR-transgenic CD4+ T cells into BALB/c hosts and observed that transgenic, but not similarly transferred wild-type, T cells were rapidly depleted. Conversely, wild-type, but not DO11.10 TCR-transgenic, CD4+ T cells were rapidly lost when transferred into DO11.10 hosts. This depletion was not related to expression of the transgenic TCR, nor was it affected by Ag-specific activation. However, T cell loss was partially abrogated if mice were depleted of either NK cells or CD8+ T cells and was completely prevented if both cell types were depleted. The authors suggest that despite extensive backcrossing, some minor histocompatibility Ags may differ between TCR-transgenic and wild-type mice, raising a cautionary flag regarding the use of adoptive transfer models to study T cell responses.
HIV in Macrophage Demise
Infection of macrophages by HIV-1 can result in both establishment of a viral reservoir and apoptosis, but the mechanism of the latter is not well understood. FOXO3a is a transcription factor proposed to regulate immune cell homeostasis that is downstream of Akt-1, a kinase down-regulated during HIV-1 infection. Cui et al. (p. 898
) examined the activity of this transcription factor in HIV-1 infection and found that FOXO3a was responsible for HIV-mediated macrophage apoptosis. In vitro experiments demonstrated that HIV-1 infection of monocyte-derived macrophages decreased FOXO3a phosphorylation and induced its translocation into the nucleus through a mechanism requiring HIV-1 replication. Constitutively active FOXO3a was found to induce macrophage apoptosis, so the authors assessed whether the prevention of FOXO3a activity could prevent HIV-1-mediated apoptosis. Indeed, inhibition of FOXO3a activity by either small interfering RNA or a dominant negative FOXO3a construct strongly suppressed HIV-1-induced macrophage apoptosis. Overexpression of Akt-1 in HIV-1-infected macrophages restored FOXO3a phosphorylation, indicating that HIV-1 controls FOXO3a activity through Akt-1. These results could be applied to therapeutic interventions with the goal of preventing the establishment of HIV-1 reservoirs in macrophages.
GATA-3 Fine Specificity
The transcription factor GATA-3 is required for thymocyte development and is a "master" regulator of Th2 differentiation, but whether its unique functions vs other GATA family members are attributable to its T cell-specific expression or to distinct biochemical features is not known. Pai et al. (p. 1050
) compared GATA-3 with the nonhematopoietic transcription factor GATA-4 to determine which features of GATA-3 were responsible for its specific activities. First, they found that expression of either GATA-3 or GATA-4 in developing thymocytes could support CD4 single-positive thymocyte differentiation, suggesting that this function requires T cell-specific expression but no unique features of GATA-3. In contrast, GATA-3 but not GATA-4 could induce IL-13 production in T cells, although both molecules activated the IL-13 promoter. To test the hypothesis that distinct portions of GATA-3 might specifically control the expression of individual Th2 cytokines, the authors created fusion proteins combining various portions of GATA-3 and GATA-4. These fusion proteins allowed the authors to localize the IL-13-inducing function of GATA-3 to a 6-aa region in its post-zinc finger tail. Mutation of a single Pro residue in GATA-4 to the Met found in this region of GATA-3 was sufficient to allow GATA-4 to induce IL-13, but not IL-4 or IL-5, production. Thus, a distinct structural motif in GATA-3 can specifically regulate the production of a single cytokine.
IL-27 in Th1 Responses
Interleukin-27, a cytokine with similarity to IL-12, was initially proposed to promote Th1 differentiation, but subsequent studies in models of autoimmunity and infection have suggested that this cytokine in fact limits Th1 responses. To address this controversy, Cao et al. (p. 922
) assessed the role of IL-27 in the development of proteoglycan (PG)-induced arthritis (PGIA), a mouse model of rheumatoid arthritis that requires Th1 cells and IFN-
. First, they found that IL-27 was up-regulated in the spleens of mice with PGIA and could enhance PG-specific T cell proliferation and IFN- production in vitro. Analysis of mice deficient in IL-27R revealed greatly decreased incidence and severity of PGIA compared with controls. Protection from PGIA in IL-27R–/– mice did not correlate with levels of IL-2, IL-4, or IL-17; however, these mice had significantly lower production of IFN- and reduced levels of PG-specific IgG2a Abs vs wild-type mice. Finally, PG-immunized IL-27R–/– mice demonstrated reduced production of multiple proinflammatory cytokines. The authors suggest that amelioration of PGIA in these mice could result from the inhibition of multiple inflammatory pathways, potentially as a result of IFN- inhibition. These results indicate that, although IL-27-mediated regulation of Th1 responses is complex and equivocal in many systems, this cytokine is clearly required for the development of PGIA.
Optimizing Memory
The development of effective vaccines requires the successful induction of immune memory. Shaulov et al. (p. 1131
) assessed the relative roles of inflammation and Ag in the stimulation of primed CD8+ T cells and found that both were required for optimal recall and memory responses. This conclusion was reached by stimulating OT-1 TCR-transgenic CD8+ T cells in vitro and transferring them into four groups of naive wild-type mice: 1) untreated; 2) infected with lymphocytic choriomeningitis virus (LCMV) ("inflammation only"); 3) immunized with OVA and infected with LCMV ("Ag and inflammation"); or 4) immunized with OVA alone ("Ag only"). In all sets of recipient mice, OT-1 cells expanded; however, primed cells exposed to both Ag and inflammation had greatly augmented proliferation and survival. Similar results were obtained if OT-1 CD8+ T cells were primed in vivo before transfer into naive hosts; that is, both an inflammatory milieu and Ag-specific restimulation were required for maximal expansion of the primed T cells. Further analysis demonstrated that the resultant Ag-specific memory T cell pool was largest in mice exposed to both Ag and inflammation and that these mice exhibited superior memory recall responses on a per-cell basis. Thus, optimal CD8+ T cell expansion and memory development require sustained exposure to both Ag and inflammation.
Summaries written by Jennifer Hartt Meyers, Ph.D.
Related articles in The JI:
- Distinct Structural Requirements of GATA-3 for the Regulation of Thymocyte and Th2 Cell Differentiation
- Sung-Yun Pai, Bok Yun Kang, Amelia M. Sabadini, Emilio Parisini, Morgan L. Truitt, and I-Cheng Ho
The JI 2008 180: 1050-1059.
[Abstract]
[Full Text]
- CD8 T Cell Expansion and Memory Differentiation Are Facilitated by Simultaneous and Sustained Exposure to Antigenic and Inflammatory Milieu
- Angela Shaulov and Kaja Murali-Krishna
The JI 2008 180: 1131-1138.
[Abstract]
[Full Text]
- The IL-3/IL-5/GM-CSF Common β Receptor Plays a Pivotal Role in the Regulation of Th2 Immunity and Allergic Airway Inflammation
- Kelly L. Asquith, Hayley S. Ramshaw, Philip M. Hansbro, Kenneth W. Beagley, Angel F. Lopez, and Paul S. Foster
The JI 2008 180: 1199-1206.
[Abstract]
[Full Text]
- Estradiol Acts Directly on Bone Marrow Myeloid Progenitors to Differentially Regulate GM-CSF or Flt3 Ligand-Mediated Dendritic Cell Differentiation
- Esther Carreras, Sean Turner, Vladislava Paharkova-Vatchkova, Allen Mao, Christopher Dascher, and Susan Kovats
The JI 2008 180: 727-738.
[Abstract]
[Full Text]
- Transgenic CD4 T Cells (DO11.10) Are Destroyed in MHC-Compatible Hosts by NK Cells and CD8 T Cells
- Darragh Duffy, Sheila M. Sparshott, Chun-ping Yang, and Eric B. Bell
The JI 2008 180: 747-753.
[Abstract]
[Full Text]
- CD4+ T Cells Recognizing a Single Self-Peptide Expressed by APCs Induce Spontaneous Autoimmune Arthritis
- Andrew L. Rankin, Amy J. Reed, Soyoung Oh, Cristina Cozzo Picca, Heath M. Guay, Joseph Larkin, III, Laura Panarey, Malinda K. Aitken, Brigitte Koeberlein, Peter E. Lipsky, John E. Tomaszewski, Ali Naji, and Andrew J. Caton
The JI 2008 180: 833-841.
[Abstract]
[Full Text]
- Transcription Factor FOXO3a Mediates Apoptosis in HIV-1-Infected Macrophages
- Min Cui, Yunlong Huang, Yong Zhao, and Jialin Zheng
The JI 2008 180: 898-906.
[Abstract]
[Full Text]
- IL-27 Induces a Th1 Immune Response and Susceptibility to Experimental Arthritis
- Yanxia Cao, Paul D. Doodes, Tibor T. Glant, and Alison Finnegan
The JI 2008 180: 922-930.
[Abstract]
[Full Text]
