Researchers identify cells that might incite nerve-damaging T cells in MS
T cells don’t go rogue without provocation. Researchers have now fingered the cells that might spur one kind of T cell to launch destructive attacks in the central nervous system. The findings, published online Sunday in Nature Immunology (Ji et al., 2013), also offer an explanation for why some seemingly stable patients start to decline and for why some T cells appear to deliver opposing effects in MS.
Clinical immunologist Lars Fugger of the University of Oxford in the United Kingdom praises the work as careful and convincing. The researchers “got it right,” he says.
Although their role in triggering neural damage in MS is contentious, errant T cells are high on the suspect list (see "Altered Immunity, Crippled Neurons"). The cells help drive experimental autoimmune encephalomyelitis (EAE), a rodent disease that replicates some aspects of MS (see "Experimental Autoimmune Encephalomyelitis"). In EAE, helper T cells, also called CD4+ cells, slip into the central nervous system from the bloodstream and orchestrate the destruction of myelin, the insulation around nerves. But in the last 10 years or so, evidence from animal studies and human patients has convinced many researchers that another type of T cell is more detrimental in MS—the cytotoxic T cell, also known as CD8+ (Mars et al., 2011). Cytotoxic T cells destroy cells in our bodies that have become cancerous or infected by viruses, and several lines of evidence suggest that misdirected attacks by CD8+ cells promote MS. In people with the illness, neural lesions harbor many more CD8+ cells than CD4+ cells (Johnson et al., 2007), and CD8+ cells that target neural molecules, including myelin components, are prevalent in the central nervous system (Zang et al., 2004).
Neither kind of T cell acts spontaneously. What sets off a T cell in the central nervous system is a close encounter with an antigen-presenting cell (APC). During this tête-a-tête, the APC offers the T cell an antigen, or molecular fragment of its target. In MS, for instance, the antigen might be a shard of myelin. Researchers have discovered that certain dendritic cells (DCs), a type of immune cell known for their ability to provoke T cells throughout the body, serve up antigens to CD4+ cells in the central nervous system. But scientists hadn’t yet identified the APCs that incite CD8+ cells there.
To solve this mystery, immunologist Joan Goverman of the University of Washington, Seattle, and colleagues induced mice to develop EAE. The animals had been genetically altered so that they harbor CD8+ cells that key on a fragment of myelin basic protein, a major ingredient of myelin. The researchers programmed the cells to squirt out the compound interferon-γ when they encounter this piece, enabling the team to determine when the CD8+ cells had dallied with their APCs. Goverman and her colleagues also used a second technique to spot these cells. They crafted antibodies that allowed them to pinpoint showoff cells that display the myelin fragment on their surface and are likely to be antigen presenters.
Two kinds of cells flaunt the myelin fragment for CD8+ cells, the results revealed. One is DCs, the same cell type that activates CD4+ T cells. However, the team determined, based on the cells’ combinations of molecular characteristics, that the DCs that stimulate CD8+ T cells are unique: They belong to a group known as Tip-DCs and are interlopers in the central nervous system. Their forebears, inflammation-promoting immune cells known as monocytes, invade the brain in EAE and then specialize. Whereas other DCs hightail it for the lymph nodes when they pick up an antigen, allowing them to spread the alarm about possible danger, Tip-DCs appear to stay put. “The hypothesis is that Tip-DCs are there to act on the spot,” Goverman says.
These Tip-DCs were the only immune cells that activated CD8+ T cells in the culture dish, Goverman and her co-workers determined. However, the team showed that oligodendrocytes, brain cells that spin myelin, also serve as APCs for CD8+ cells in mice with EAE. Oligodendrocytes don’t normally produce MHC, the molecular apparatus required to display antigens to cells of the immune system, but they do manufacture MHC during inflammation triggered by the CD4+ cells, the researchers found. That ability might enable the brain cells to stimulate CD8+ cells with pieces of their own myelin—and to become targets for those CD8+ cells.
“It’s a beautiful study that shows how CD8+ cells can be activated by two kinds of cells in the central nervous system,” Fugger says. “It shows another layer of what’s going on in the central nervous system in a mouse model.” The work also suggests that a second T cell culprit emerges as EAE—and possibly MS—progresses. “This is the first indication that tissue destruction induced by a CD4+ cell could spread to a CD8+ cell,” says immunologist Stephen Miller of Northwestern University Feinberg School of Medicine in Chicago. Previous studies have revealed that the T cells that spark EAE respond to different fragments of myelin than those recognized by the T cells that infiltrate the nervous system later in the illness. The paper suggests how this change could occur as inflammation lures CD8+ cells into the nervous system. Miller notes that this target switching could make it harder to treat MS: “This is extremely important if we hope to ever use an antigen-specific therapy for MS.”
The results don’t point to specific MS treatments, Goverman says, but they do suggest an explanation for a shift in MS severity that doctors often observe. Many patients who suffer from relapsing-remitting MS, in which symptoms wax and wane, eventually develop secondary progressive MS, in which their physical condition continually worsens. Relapsing-remitting patients tend to show brain lesions, but they often disappear after the conversion to secondary progressive MS, even though neural damage continues to accumulate.
The transition between these two disease phases might represent the point when CD8+ cells move into the central nervous system and start taking over from CD4+ cells, the researchers hypothesize. “You now have cells that are equipped to kill,” Goverman says. The CD8+ cells begin causing more severe damage than do the CD4+ cells, and nerve deterioration accelerates.
But the team proposes that the CD8+ takeover could also quell inflammation and reduce brain lesions. CD8+ cells might attack not only oligodendrocytes that carry myelin antigens—thus harming nerves—but also the myelin-bearing DCs themselves, which provoke inflammation. This duality might reconcile the seemingly contradictory results from previous studies, which have found that CD8+ cells play positive and negative roles in EAE.
The researchers plan to test the possibility by following CD8+ cells in mice to determine whether they kill oligodendrocytes and DCs. “We want to find out what they do once they get in” to the central nervous system, Goverman says. The work might reveal whether CD8+ T cells can protect and provoke at the same time.
Key open questions
- Do cells other than oligodendrocytes and dendritic cells stimulate CD8+ T cells in the nervous system?
- What spurs monocytes to develop into Tip-DCs instead of other DC varieties?
- Other DC varieties often congregate in lymph nodes after picking up an antigen. Why don’t Tip-DCs follow suit?
Thumbnail image on landing page. "Molecular basis of T-cell-mediated immunity" by Davide.pirolli, 2012. Released under Creative Commons Attribution-ShareAlike 3.0 Unported (CC BY-SA 3.0) license.