The Innate Immune System’s Secret Weapon

When a pathogen enters the body and begins multiplying, the immune system has to respond with haste. However, adaptive immune cells—so-named because they can recognize, respond to, and remember specific microbes—require four to seven days to mount a tailor-made defensive.¹ Meanwhile, innate immune cells, which recognize general signs of a threat, such as common bacterial lipids, strike immediately and buy time for the adaptive immune system to prepare its attack. Immunologists have long accepted the “innate-first, adaptive-second” model of the immune response, but following an odd discovery 15 years ago, the line separating the innate and adaptive axes began to blur.² Scientists uncovered a new group of immune cells called innate lymphoid cells that elicit similar responses to the adaptive arm’s T cells, mainly by triggering inflammation through the secretion of chemical signals called cytokines. However, like other innate cells, they are unable to recognize specific antigens. This means they can respond immediately to new threats, like pathogens or cancers, and immunologists are looking to harness them for therapies.

The Early Cell Catches the Worm

The year was 2010, and immunologist Andrew McKenzie and his team at the University of Cambridge were studying how the immune system fights intestinal worm infections in mice. At that time, immunologists thought T cells were mainly responsible, in part because they secrete a protein called interleukin-13 (IL-13) that triggers mucus secretion in the gut, which helps to expel worms.³ However, McKenzie noticed that mice could clear the infection surprisingly quickly. “If it takes seven days for the T cells to get going, and the worms are expelled after five days, something else must be making IL-13,” he said.

He began searching for novel parasite-fighting immune cells. McKenzie knew that IL-25 triggers a class of T cells called type-2 helper T cells (Th2s) to proliferate and produce IL-13, and he wondered if IL-25 also triggered the unidentified anti-parasite immune cells to produce IL-13 in the same way.⁴ When his team administered IL-25 to one group of mice, they found that these mice had larger populations of IL-13-secreting immune cells that weren’t T cells, suggesting IL-25 caused these previously unidentified cells to proliferate.⁵ These novel cells didn’t possess any antigen-specific receptors, indicating that they belonged to the innate immune system. McKenzie named the new IL-13 producers “nuocytes” because “nu” is the 13^th letter of the Greek alphabet, but the name didn’t stick. Today, scientists call them type-2 innate lymphoid cells (ILC2s).

In the years that followed, other groups identified more types of innate lymphoid cells and noticed a peculiar pattern: For every class of T cell, an ILC counterpart exists that resembles it.⁶ For example, both type-1 helper T cells (Th1s) and ILC1s mount a similar immune response against viruses and other intracellular parasites by secreting a signature set of cytokines. Following the trend, ILC2s and Th2s elicit a similar response against extracellular parasites like worms; ILC3s and Th17s both safeguard mucosal barriers, such as the gut; and natural killer cells (NKs)—another type of ILC—fill in for killer T cells that target cells for destruction. In each of these ILC and T-cell pairs, the same transcription factors drive their differentiation, which at least partly explains why they adopt similar functions.

Spot the Differences

Despite their many similarities to T cells, ILCs lack a key feature that make T cells adaptive. They cannot recognize specific antigens, which means they lack the marksmanship to attack diseased cells while leaving healthy bystanders unharmed.⁷ They also make their appearance during the immediate, innate phase of the immune response rather than during the delayed, adaptive phase. By performing immune functions historically associated with the antigen-specific, adaptive response in an imprecise manner during the innate stage, ILCs seemingly disrupted the innate-then-adaptive model for fighting an infection.⁸

ILCs and T cells differ in other ways, too. T cells tend to circulate around the body, but ILCs tend to reside in tissues, with the exception of NK cells.⁹ Jenny Mjösberg, an immunologist at the Karolinska Institute, said that usually all ILC types are present in a tissue, but the relevant type will respond during an infection. For example, a parasite will trigger the epithelium to release the cytokine IL-25, which activates ILC2s, whereas a viral infection will cause cells to secrete IL-12, triggering ILC1s.^10,11

Besides performing T-cell functions early, they may play important roles in regulating inflammation.¹² “We often think of the immune system as fighting things, but the reality is the immune system is keeping everything in balance on a day-to-day basis,” said Gabrielle Belz, an immunologist at the Frazer Institute at the University of Queensland. For example, ILC2s could play an important role in regulating allergies, Mjösberg said.¹³ She explained that some people constantly suffer with allergic responses even if they are not exposed to an allergen like pollen. “In these patients, you likely just have an exaggerated ILC2 response,” she said. This occurs because, unlike Th2s, ILC2s don’t respond to specific antigens (allergens in this case) but to general warning signs, such as bacterial lipids or to the presence of cytokines, such as IL-25, so they could trigger an allergy even in people who have not come into contact with pollen or other allergens.

Even after T cells are activated, ILCs continue to play an important role in the immune response by recruiting T cells to threats, and producing cytokines that keep them active.¹⁴ “We know that ILCs produce cytokines that are really important to program a subsequent adaptive immune response,” Mjösberg said. “I see them a bit as setting the stage for T cells,” she added. For example, ILC2s help recruit T cells to tumors, perhaps by secreting chemokines—cytokines that T cells migrate toward. Once T cells arrive at the cancer, pro-inflammatory cytokines secreted by the ILCs might also help keep the T cells active. This led immunologists to explore the potential for using ILCs in cancer immunotherapy.

Tumor Takedown

Harnessing immune cells to fight cancer is a growing clinical practice. An immunotherapy called adoptive cell transfer involves removing T cells from a cancer patient, stimulating them to proliferate outside the body, and returning them to the patient to overwhelm the tumor.¹⁵ Wilfred Jefferies, an immunologist at the University of British Columbia, is exploring the potential to do the same with ILCs. Although ILCs cannot recognize tumor antigens, they can detect signs of cancer, such as tumor-associated inflammation. This enables them to mount an anti-cancer response, making them potential therapeutic candidates.

It all started when Jefferies’s team found that the cytokine IL-33 plays an important role in helping T cells to fight solid lung tumors. “We were interested in what IL-33 actually regulates,” Jefferies said. Other researchers had previously shown that this cytokine activates ILC2s, so Jefferies transferred a small number of these cells into mice with lung cancer.¹⁶ They found that these innate immune fighters significantly shrank the tumors by recruiting T cells to the cancer, narrowing the focus of the T cells to the tumor.¹⁷

Per cell transferred, Jefferies said the ILC2s proved 150 times more effective than T-cell based therapies in mice. He cautions, however, that, “It's not clear whether this will be transferable to patient populations or not.” He said, “We've only studied a single type of tumor, so it's possible that this isn't relevant for some tumor cell types.”

Adoptive transfer with ILCs instead of T cells could have important advantages. Since T cells recognize antigens, this increases the risk that adoptively-transferred T cells could cross-react with so-called self-antigens, which are innocuous proteins present on the patient’s healthy cells.¹⁸ This could trigger an autoimmune reaction that could harm the patient. Using ILCs may lower the risk since they lack antigen recognition. It also simplifies the process of adoptive cell therapy: When clinicians extract T cells from the patient, they have to isolate the kind that recognizes the tumor, which means they have to find the tumor antigen and use it to purify the relevant T cell—a time-consuming process.¹⁹ These steps disappear when working with ILCs.

Fifteen years on, scientists continue to unravel the mysteries of these cells. “Originally, we thought, ‘they don’t have antigen specific receptors, so they just get triggered by everything.’ But that seems not to be the case either,” Belz said. Understanding their regulation will prove crucial for adoptive cell therapy. “You can't just inject these cells and hope that they don't lead to massive inflammation and collateral damage," Mjösberg said. Jefferies echoed this point and stressed that it is one reason clinicians aren’t close to using ILCs in the clinic. “We know a lot about what activates them, but there is still quite a lot to be discovered about their inhibitory signals,” Mjösberg added.

The innate-then-adaptive model of immunity implies that each axis employs distinct tactics depending on whether they indiscriminately target whole tissues or pinpoint strikes on diseased cells. ILCs obscure the distinction by eliciting a general, imprecise reaction using functions typically associated with the antigen-specific adaptive response. Beyond serving as a potential therapeutic against cancers, these elusive cells force immunologists to question the tidy separation between innate and adaptive immunity.

Disclosure of Conflicts of Interest

Wilfred Jefferies is a founder and equity holder in Cava Healthcare Inc., a company developing adoptive cell ILC therapies. He is also an inventor on the patent for this technology.

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