There are two major haplotypes of signal lymphocytic activation molecule (
Slam) in inbred mouse strains, with the
Slam haplotype 1 expressed in C57Bl/6 mice and the
Slam haplotype 2 expressed in most other commonly used inbred strains, including 129 mice. Because signaling through Slam family receptors can affect innate immunity [natural killer T cell (NKT) and γ-δ T-cell receptor], and innate immunity can determine susceptibility to coxsackievirus B3 (CVB3) infection, the present study evaluated the response of C57Bl/6 and congenic B6.129c1 mice (expressing the 129-derived
Slam locus) to CVB3. CVB3-infected C57Bl/6 male mice developed increased myocarditis but reduced hepatic injury compared with infected B6.129c1 mice. C57Bl/6 mice also had increased γδ
+ and CD8
+interferon-γ
+ cells but decreased numbers of NKT (T-cell receptor β chain + mCD1d tetramer
+) and CD4
+FoxP3
+ cells compared with B6.129c1 mice. C57Bl/6 mice were infected with CVB3 and treated with either α-galactosylceramide, an NKT cell-specific ligand, or vehicle (dimethyl sulfoxide/PBS). Mice treated with α-galactosylceramide showed significantly reduced myocarditis. Liver injuries, as determined by alanine aminotransferase levels in plasma, were increased significantly, confirming that NKT cells are protective for myocarditis but pathogenic in the liver.Myocarditis is an inflammation of the cardiac muscle that follows microbial infections.
1 Among viruses, enteroviruses including coxsackie B viruses are common etiologic agents.
2,3 Although infectious agents act as a trigger for myocarditis, there is considerable debate as to the actual mechanism(s) of myocardial injury. Viruses directly cause cellular dysfunction either through induced cell death, shut down of cell RNA and protein synthesis, or viral protease cleavage of contractile proteins.
4,5 In addition, cytokines such as IL-1β, IL-6, and tumor necrosis factor α, which are elicited from resident cells in the heart subsequent to infection, can suppress contractility, leading to cardiac dysfunction.
6 Finally, host immune responses to infection may kill myocytes, leading to cardiac stress. Host response can be directed specifically toward virally infected cardiocytes or infection can trigger autoimmunity to cardiac antigens (autoimmunity), which destroys both infected and uninfected myocytes.
7Host innate immune responses occur rapidly, subsequent to viral infections, and usually have broad specificity, unlike the classic adaptive immune response, which requires a week or more for development of a measurable response in the naive individual but is highly specific to the inducing pathogen. The innate immune response both helps to control microbe load before generation of the adaptive immune response and has a major impact on the phenotype and intensity of the adaptive response. Two types of T cells representing innate immunity are natural killer T cells (NKT) and T cells expressing the γ-δ T-cell receptor (γδ
+). A study by Wu et al
8 showed that
in vivo administration of α-galactosylceramide, a ligand that specifically activates NKT cells, protects mice from coxsackievirus B3 (CVB3)-induced myocarditis. Prior studies have shown that signaling through Slam family receptors has a major impact on NKT cell development,
9–11 and that different
Slam haplotypes can have distinct effects on NKT cell response and function.
9,12 There are two major
Slam haplotypes,
Slam haplotype 1 and
Slam haplotype 2, that distinguish commonly used inbred mouse strains.
13,14
Slam haplotype 1 is present in C57Bl/6, and
Slam haplotype 2 is present in most other commonly used mouse strains including 129S1/SvImJ and BALB/c mice. The congenic B6.129c1 mouse expresses the genetic region of chromosome 1 containing the 129-derived
Slam haplotype 2 locus on the C57Bl/6 background and was used previously to show
Slam haplotype control of liver NKT cell numbers and NKT cell cytokine production.
12 In addition,
Slam haplotypes previously were shown to regulate macrophage tumor necrosis factor production in response to lipopolysaccharide.
12 Although less well studied, Slam family–receptor signaling also has been shown to affect γδ
+ T-cell development. Studies using human peripheral blood mononuclear cells stimulated
in vitro with antibody to CD3 and either IL-2, anti-CD150 (SLAM), or IL-15 showed that all three stimulation protocols resulted in γδ
+ T-cell survival. However, co-culture with anti-CD3 and anti-CD150 resulted in selective proliferation of CD8
+CD56
+γδ
+ T cells expressing the Vδ1 chain, and cells co-cultured with anti-CD3 and IL-15 resulted in preferential generation of CD8
−CD56
−γδ
+ cells expressing the Vδ2 chain.
15 Therefore, SLAM signaling can impact the generation of a subpopulation of the total γδ
+ cell population in humans. Prior studies from the Huber laboratory have shown that a subpopulation of γδ
+ cells is crucial to myocarditis susceptibility subsequent to CVB3 infection
16 and that the relevant γδ
+ cell expresses both CD8 and the Vγ4 chain.
16,17 This raised the question of whether
Slam haplotypes modulated selected γδ
+ cell subsets in the mouse, as it does in humans, and whether the
Slam haplotype specifically could affect activation of the CD8
+Vγ4
+ T cell, which is known to be pathogenic in CVB3-induced myocarditis.CVB3 infection of mice results in multiple organ infection, including pancreas, liver, and heart with accompanying tissue injury in all tissues. There are well-established differences in disease susceptibility between BALB/c and C57Bl/6 mice, strains expressing the two distinct
Slam haplotypes. C57Bl/6 mice are highly susceptible to type 2 autoimmune hepatitis and develop extensive hepatic inflammation, whereas BALB/c mice are resistant to this disease and show no inflammation.
18 In contrast, BALB/c mice are more susceptible to myocarditis
19–22 compared with the more resistant C57Bl/6 strain. However, there are many genetic differences between BALB/c and C57Bl/6 mice, which may influence disease development or development and activation of specific innate effectors such as NKT and γδ T cells. The goal of the current study was to determine whether
Slam haplotype affected NKT and Vγ4
+ T-cell responses subsequent to CVB3 infection using C57Bl/6 congenic mice in which the
Slam locus alone differed between the mouse strains, and whether haplotype-dependent NKT/Vγ4
+ cell response had a distinct effect in different organs infected with the virus in the absence of the many other genetic differences between BALB/c and C57Bl/6 mice.
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