Wednesday, November 30, 2011
Monday, November 28, 2011
Sunday, November 27, 2011
Saturday, November 26, 2011
Tuesday, November 22, 2011
Saturday, November 19, 2011
γδ T cells are a subset of T cells that bridge innate and adaptive immunity. γδ T cells bind and recognize a broad range of foreign materials with their “γδ” receptors. These foreign entities can include proteins and lipids from pathogens as well as host stress molecules. This is the innate part of their function; it is fairly non-specific. They then generate either CTL-like (toxic) or Th-like (helper) responses against these pesky materials. This is the adaptive part of their function; it is more specific (1). Often, it is thought that all γδ T cells behave similarly, in the way that was just described.
A growing body of evidence, however, including a recent paper by Yin et. al. (2), suggests that different subsets of γδ T cells perform unique functions (3). In their work, Yin and coworkers found that one type of γδ T cell, Vg1 γδ T cells, inhibits the antitumor response of another type of γδ T cell, Vγ4 γδ T cells. (Vγ1 and Vγ4 refer to a particular gene segment that codes for part of the receptor chain; think of it as a receptor flavor).
In a previous study (4), Yin and coworkers found that Vγ4 γδ T cells killed tumors using INFγ (a signaling molecule that can: tell other cells to kill the tumor, prevent blood and nutrient flow to the tumor, and prevent spreading of the tumor by constructing a barrier around it (1)) and perforin (a molecule that kills a tumor by poking holes in it (1)). In this study, Yin et al. found that Vγ1 γδ T cells inhibit the anti-tumor response of Vγ4 γδ T by using signaling molecule IL-4.
Yin and co-workers placed Vγ1 γδ T cells , Vγ4 γδ T cells, and tumor cells in mice in different combinations and monitored tumor growth. Vγ4 γδ T cells alone suppressed the tumor. Addition of Vγ1 γδ T cells reduced this suppression. They obtained similar results when they performed the experiments in vitro (outside of mice, in culture).
When they separated the two types of cells by a membrane in vitro, they observed the same loss of tumor suppressor function. This suggests that the Vγ1 γδ T cells do not depend on direct cell-to-cell contact to inhibit Vγ4 γδ T cells and instead depend on a soluble mediator. This conclusion was further confirmed by a dye staining experiment that showed that the two types of cells localized to different parts of the tumor and were therefore unlikely to directly contact each other at all.
The soluble mediator molecule was determined to be IL-4. Suppressing IL-4 restored Vγ4 γδ T tumor suppression abilities. Furthermore, adding IL-4 alone, but not Vγ1 γδ T cells, to Vγ4 γδ T cells suppressed antitumor properties. The relationship between the two cell types came full circle when Yin and coworkers found that IL-4 down regulates NKG2D (Natural Killer Group 2 receptor, common to NK cells and γδ T cells), a receptor that tells Vγ4 γδ T cells to make IFNγ and perforin. IL-4 interferes with IFNγ and perforin. Thus, molecules made by Vγ1 γδ T cells interfere with molecules made by Vγ4 γδ T cells.
The study leaves some questions unanswered. For example, why do the different γδ T cell subsets localize to different parts of the tumor? How does IL-4 down regulate NKG2D receptors? More broadly, how do Vγ4 γδ T and Vγ1 γδ T cells interact with other cell types? But it also provides novel and potentially useful results. It suggests that Vγ1 γδ T is a regulatory T cell of sorts in that it dampens the response of another type of T cell, Vγ4 γδ T. The study also opens the door for a possible tumor therapy where Vγ1 γδ T cells are selectively killed or inactivated so that Vγ4 γδ T cells can be allowed to carryout out their tumor-killing mission.
Yin, Z. et. al. 2011. Regulatory Role of Vγ1 γδ T cells in Tumor Immunity through IL-4 Production. J. Immunol. 187: 4979-4986.
(1) Mak, Tak and Mary Saunders. Primer to the Immune Response. California: Elsevier, 2011. Print.
(2) Yin, Z. et. al. 2011. Regulatory Role of Vγ1 γδ T cells in Tumor Immunity through IL-4 Production. J. Immunol. 187: 4979-4986.
(4) He, W. , J. Hao, S. Dong, Y. Gao, J. Tao, H. Chi, R. Flavell, R. L. O’Brien, W. K. Born, J. Craft, et al. 2010. Naturally Activated Vγ4 γδ T cells Play a Protective Role in Tumor Immunity through Expression of Eomesodermin. J. Immunol. 185: 126–133.
Thursday, November 17, 2011
A common form of allergy is immediate hypersenstivity, or type I hypersensitivity. This response to an allergen usually occurs relatively quickly (~ 30 mins) and can be very severe. Such a hypersensitivity (aka allergy) is mediated in two distinct steps. First is the sensitization stage where the allergen penetrates, most likely at a skin or mucosal interface, and is taken up by dendritic cells (DC), which are known for there extensive processes and ability to showcase a pathogen on their surface. Next, the DC activates a helper T cell and helps produce a polarized response, meaning the T cell develops into a Th2 subtype. A danger signal must be present in order for this type of activation to occur, but the whereabouts of such a signal is still under debate. Nevertheless, the Th2 cell, known for aiding in the humoral (antibody response) does its duty and activated B cells. These B cells ultimately undergo a process dubbed isotype switching where the type of antibody they produce is modified. This process leads to B cells producing large quantities of a type of antibody known as IgE, known for its role in allergies.
The next stage is the effector stage where if the allergen returns to the body it leads to an allergic response. The IgE antibodies can bind to the outer surface of certain leukocytes, such as mast cells, via Fc receptors and "arm" them. When the allergen returns then the mast cell is activated via the antibodies and degranulates, spewing toxic chemicals at the allergen and causing an immune response in the process.
In the recent work of Morin et al. (2011), the group examines the allergenicity of two proteins found in different fractions of cow milk, beta-lactoglobulin (BLG) and casein (CAS). Cow's milk allergy (CMA) is very common during early childhood and evokes a rapid response. However, CMA usually disappears , it remains in some (Sicherer et al. 2010). What is more dangerous about CMA is that it increases the child's susceptibility to other allergies (Saarinen et al. 2005). In this study, they examined the allergenic and immunogenic effects of these two proteins in two different strains of mice, one was germ-free (GF) and the other conventionally raised (CV). They attempted to complete this study in the absence of an adjuvant for the proteins. Adjuvants are commonly used to give the immune system a push, so to speak, helping to evoke an immune response to the injected compound. The downside of adjuvants in allergy studies is that they can evoke non-specific allergies to some of their own components, making it difficult to examine the specificity of a response. The GF mice have an immature immune system due to their lack of experience with many pathogens, so the authors hypothesized these mice would be more susceptible to an allergic response. Two sets of experiments were completed in each mouse, one measuring antibody type from blood samples and the other examining cytokine secretion from the isolated and reactivated spleens of the mice. Afterwards, they tried something novel and intraperitoneally administered a heated mix of the proteins, hoping to denature the proteins and open new epitopes for binding.
Tuesday, November 15, 2011
Tuesday, November 8, 2011
Friday, November 4, 2011
To understand the role of IRF-1, Brien et al. (2011) assessed WNF infectivity in IRF-1 normal and IRF-1 deficient mice (1). As previously mentioned, they chose to manipulate IRF-1 because mice lacking it (IRF-1-/- ) were vulnerable to WNV infection. First, it was confirmed that IRF-1 is required for control of lethal WNV infection. After infection with WNV, Wild-type (WT) mice had a 65% survival rate and a mean time to death of 11 days, whereas IRF-1-/- mice had a 0% survival rate and a mean time to death of 9.5 days.
To better understand how IRF-1 deficiency is a disadvantage for mice with WNV infection, the ‘viral burden’ was measured at various points post infection in serum, several peripheral organs, and the central nervous system (CNS). Indeed, increased levels of viral RNA were found in the serum and lymph nodes in IRF-1-/- mice compared to the WT. Therefore, IRF-1 controls the early stages of WNV infection. Additionally, WNV infected the spleen more rapidly and clearance was delayed in IRF-1-/- mice. WNV was also detected sooner in the kidneys of IRF-1-/- mice, further suggesting that IRF-1 normally functions to control infection in peripheral tissues.