In this issue
Abstract
Cover Pictures
The cover image features a frozen section from an embryonic day 16 mouse spleen stained by immunofluorescence to demonstrate the presence and location of lymphoid tissue inducer (LTi) cells. Withers et al.
show that these cells form the focus of lymphocyte accumulation in the developing mouse spleen. Red staining for CD45 marks haemopoietic cells, green shows IL-7Rα expression, and CD4 expression is in blue. LTi cells that express all markers (in white) cluster around blood vessels in the embryonic spleen where signalling to stromal cells initiates lymphocyte recruitment.
No spotlight for LIME in T and B cell signaling
Transmembrane adaptor proteins (TRAP) are located in membrane rafts, and at least one - LAT (linker for activation of T cells) - is key for T cell development and function. In vitro studies have indicated that LIME (Lck-interacting membrane protein), another TRAP, is located at the T cell-APC interface and might be involved in signaling via both T cell and B cell receptors. To gain further insight into the function of LIME in vivo, Grégoire et al. generate LIME-deficient mice. In both LIME-deficient and LIME/NTAL double-deficient mice (NTAL being yet another TRAP), absolutely no effect on T or B cell development or function is detected. Only in TCR-transgenic mice is a slight enhancement of positive selection detected in the absence of LIME. When it comes to signaling in lymphocytes, it seems that - among the TRAP - LAT steals the show.
Those pesky sand flies - a new vaccination strategy against Leishmania infection?
As sand flies, the vectors for Leishmania parasites, probe for their next meal, they also inject their saliva into the hosts. In both animal models and individuals from endemic areas, anti-saliva immune responses have been detected, and there is evidence that such responses may favor - or impair - host anti-Leishmania responses. Vinhas et al. investigate anti-saliva responses in non-Leishmania- infected human volunteers using laboratory-raised Lutzomyia longipalpis, the sand fly vector of Leishmania chagasi (the primary perpetrator of visceral leishmaniasis). Sand fly bites induce both humoral (anti-saliva IgG1, IgG4 and IgE) and cellular (IFN-γ- and IL-10-producing PBMC, and increased frequencies of CD25+ T cells) immune responses. Most impressively, after a “sand fly boost” 1 year later, the volunteers demonstrate impressive humoral and cellular anti-saliva immunity that corresponds with decreased infection of macrophages with Leishmania in vitro. Perhaps sand flies can be used to fight the infection they spread…… an interesting perspective.
Maintenance of CD8+ T cell memory: IL-7 is reprieved from a sentence of mere redundancy
While a crucial role for IL-15 in the maintenance of CD8+ T cell memory seems clear, the part that IL-7 plays is still controversial: does IL-7 have an active role, or does it just overlap with the dominant function of IL-15? Studies using IL-7-/- mice are complicated by defects in T cell development, with functional abnormalities and lymphopenia in the periphery. To address this, Carrio et al. engineer expression of the IL-7Rα transgene in the thymus of IL-7-/- mice, which restores T cell development, filling the periphery with normal numbers of functional T cells. Although the T cells are unresponsive to IL-7, normal memory cell development can be observed; however, after transfer of the functional T cells into wild-type recipients, the generated memory cells are not maintained. Furthermore, with IL-15-/- mice as the recipients the poor memory cell persistence is even more dramatic. Thus, IL-7 is not just an “understudy” waiting patiently backstage, it appears to work in concert with IL-15 in the maintenance of memory CD8+ T cells.
Focusing in on a role for ADAP in conventional thymic selection
The protein tyrosine kinase ADAP (adhesion and degranulation-promoting adapter protein) is expressed by a variety of cell types (T cells, NK cells, platelets, myeloid cells), and studies have particularly indicated its participation in TCR signaling, but many features of ADAP expression and function have not yet been addressed. Dluzniewska et al. find that expression of ADAP on thymocytes changes profoundly during their development in the thymus, with ADAP expression levels especially increasing during the transition from the double-positive to single-positive (SP) stage, when positive selection occurs. Indeed, confirming previous studies, Dluzniewska et al. find that in radiation chimeras fewer ADAP-/- thymocytes than wild-type thymocytes reach the SP stage. In addition, the authors show that while ADAP is also expressed by non-conventional thymocytes (NKT, CD8αα, TCRγδ), it does not contribute to their development. Interestingly, however, further investigation using the radiation chimeras indicated a role for ADAP in the homeostasis or migration of CD8αα cells in the intestine. Thus, while ADAP has a relatively wide expression pattern in hematopoietic cells, its function seems to center around thymic selection of TCRαβ T cells and, possibly, homeostasis of CD8αα IEL.
Oh where, oh where do the central memory T cells go (during chronic viral infection)?
For chronic persistent infections such as CMV, specific CD8+ central memory cells (TCM) are hardly detectable in the peripheral blood (PB). This seems surprising, as TCM are thought to be more important than effector memory cells (TEM) for maintaining long-term immunity. So where are the TCM? Letsch et al. examine paired human PB and BM samples and find that, although the overall frequency of CMV-specific CD8+ T cells detected in the two compartments is nearly identical, the distribution of effector (TEff) and memory (TCM, TEM) subsets is very different, with a substantial population of CMV-specific CD8+ TCM being present in the BM. In addition, upon in vitro stimulation, CMV-specific cells from the BM expand more efficiently than those from PB, a finding that holds promise for the expansion of CMV- (and other) specific cells for adoptive transfer.
