| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Regulating Mast Cell Maturation
|
RI surface expression and downstream messenger phosphorylations seen in wild-type CTMCs were negligible in mutant cells. The experiments indicate that NDRG1 regulates maturation and degranulation of mouse mast cells in vivo and ex vivo. How Vitamin D Kills TB
Treatment with antimicrobial agents has led to an increase in drug-resistant Mycobacterium tuberculosis (MTB). However, before the development of antimicrobial agents, sunshine and cod liver oil were standard treatments for TB. Martineau et al. (p. 7190
) found that in vitro addition of the active vitamin D metabolite, 1
,25(OH)2D3, to human PBMCs infected with an avirulent or virulent strain of luminescent-tagged MTB lowered the luminescence ratio and CFUs. Suppression at the nuclear, but not the membrane, vitamin D receptor was demonstrated using agonists specific for each receptor. Incubation of PBMCs with 1,25(OH)2D3 abolished or reversed MTB-induced increases in IL-12, IFN-
, or TNF mRNA expression. Although expression of mRNA for NO synthase was elevated in 1,25(OH)2D3-treated MTB-infected PBMCs, addition of an inhibitor of reactive nitrogen intermediates did not increase the luminescence ratio. 1,25(OH)2D3 reversed the decreased expression of the antimicrobial peptide LL-37 in MTB-infected human mononuclear cells and PBMCs as measured by RT-PCR and immunohistochemical staining. An LL-37-mediated decrease in MTB CFU occurred only in cultures depleted of iron required by the bacteria for ATP generation. The authors propose that vitamin D protects against TB by increasing transcription of the gene encoding the antimicrobial peptide LL-37 rather than by conventional cytokines or reactive nitrogen intermediates.
Multiple Treg Cell Lineages
Several lines of evidence suggest that there are distinct subsets of FoxP3+ regulatory T cells (Treg). In their study on p. 6901
, Stephens et al. found activated (CD62LlowCD103+) TCR 
+FoxP3+ Treg cells in the periphery of MHCII–/– and CD4–/– mice, although the numbers were fewer than the naive Treg cells found in MHCI–/– or wild-type mice. A low number of activated Treg cells were found in MHCI–/–/MHCII–/– mice. Effector CD103+ Treg cell totals were equal in all but MHCI–/–/MHCII–/– mice. The percentages of CD4+CD8–, CD4+CD8+, and CD4–CD8+ cells varied among the strains; mice lacking both MHC molecules had only CD4+CD8–. Effector Treg cells represented 15–20% of Fox P3+ thymocytes in wild-type and MHCI–/– mice, nearly all in MHCII–/– mice, the majority in CD4–/– mice, and none in MHCI–/–/MHCII–/– mice; all Treg thymocytes were CD62Lhigh. Selection of naive, but not effector, CD4+CD8– Treg thymocytes occurred in mice expressing MHC class II only on thymic cortical epithelium. Peripheral effector Treg cells proliferated more than naive cells, as measured by BrdU incorporation and CFSE dilution of adoptively transferred cells, and had higher rates of apoptosis. Peripheral effector Treg cells expressing two NK cell markers were found in all strains and dominated in MHCI–/–/MHCII–/– mice or in wild-type mice treated with anti-MHC class II Abs. Ex vivo, naive CD103+ or CD103– Treg cells from wild-type, MHCII–/–, or MHCI–/–/MHCII–/– mice suppressed proliferation of nonspecifically stimulated CD4+CD25– HA-specific TCR T cells. HA peptide-stimulated cells were suppressed by wild-type, but enhanced by MHCII–/–,CD103– Treg cells. CD103+ Treg cells were increased 
5-fold in lymph nodes draining LPS injection sites. The authors use the cell marker CD103+ and several MHC-deficient mouse strains to identify unique effector FoxP3+ Treg cell subsets of thymic and extrathymic origins.
Chromatin Remodeling in T Cells
|
Treg TCR Repertoires
|
gene, a TCR LTD minilocus, and a homozygous knockout of the endogenous TCR gene. LTD mice consequently generate CD4+ T cells of limited diversity. Treg and Tconv populations had comparably diverse TCR repertoires with certain high frequency sequences. The repertoires were distinct but had significant overlap; distributions of CDR3 lengths were similar, but those of Treg cells were more positively charged. By similar analyses, CD4+CD25–FoxP3+ Treg cells were more closely related to Treg than to Tconv cells. The TCR repertoire patterns of single-positive Treg and Tconv thymocytes were similar but differed from those of peripheral cells. Introduction of the H2-DM–/– mutation into the LTD mouse (LTD.DM–/–) resulted in shorter CDR3 loops and joining sequences in CD4+ thymocytes and a diverse TCR repertoire that was distinct from that of DM+/+ controls. Short CDR3 loops survived only in DM–/– into DM–/– chimeras but not in other chimera combinations with DM+/+. In vivo, LTD.DM–/– T cells carrying the unique CDR3 sequences divided in wild-type, but not in DM–/–, hosts. Peripheral Treg and Tconv repertoires were reduced to similar extents in LTD.DM–/– vs wild-type mice, but the Treg increase in positively charged CDR3 motifs did not occur. The authors conclude that TCR repertoires of Tconv and Treg cells in mice are shaped by negative selection of MHC/peptide combinations. Virus Dose and Antiviral Responses
The influence of virus inoculation dose vs bystander events in antiviral CD8+ T cell responses has not been explored in depth. On p. 7267
, Andrews et al. followed CD8+ T cell expansion in the mouse model of persistent polyoma virus (PyV) infection. Infection with a low dose of virus resulted in a 2-day delay in peak expansion of CD8+ T cells specific for the dominant PyV epitope in mice compared with a high dose of virus. Reduced inflammatory responses 2 days postinfection were seen in lymph nodes of mice given the low virus dose. During the acute and chronic phases of infection, more T cells from mice infected with the low, vs the high, virus dose expressed IL-7R, produced more IFN-, and expressed less of an inhibitory receptor. Both virus doses elicited the same TCR V usage and functional avidity. More CD8+ T cells from the low-, vs high-, dose virus infection coproduced IL-2 and TNF- during the chronic phase and had a greater in vivo recall response to challenge with the dominant viral epitope. CSFE-labeled spleen cells from virus-infected mice were transferred into recipients infected with PyV lacking the dominant viral epitope; cells from mice infected with low-dose virus survived longer than those from mice infected with high-dose virus. The amount of dominant viral peptide used to load dendritic cells injected into naive mice did not affect the phenotype or function of the anti-PyV CD8+ T cell response, but recipients subsequently infected with high-, vs low-, dose virus generated fewer Ag-specific CD8+ T cells and had lower IFN- responses. The authors propose that memory anti-PyV CD8+ T cell numbers and function are improved with low virus dose and with reduced bystander inflammation during the early phases of infection.
Where Are You?
|
Summaries written by Dorothy L. Buchhagen, Ph.D.
Related articles in The JI:
- and TNF-Independent Vitamin D-Inducible Human Suppression of Mycobacteria: The Role of Cathelicidin LL-37
| ||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
