Well equipped

How immune cells remain metabolically flexible over time

September 22, 2017

During an immune response T cells depend on flexible metabolism to effectively clear infections and provide long-lasting immune protection. Research by the Max Planck Institute of Immunobiology and Epigenetics in Freiburg (MPI-IE) provides new insight into how signals by CD28 during activation equip T cell mitochondria with metabolic flexibility. The study from the laboratory of Erika Pearce, published in the journal Cell, suggests that this is part of the secret to establishing memory T cells able to provide long-lasting immune protection.

T cells are critical components of the immune system that protect us against infection and cancer. T cell responses develop following exposure to infectious organisms, or the emergence of malignant cells, and characteristically progress in two phases. Initially, T cells proliferate and differentiate into short-lived effector T cells that function to prevent disease development. This activation step requires stimulation of the T cell receptors that recognizes foreign antigen and usually occurs in the presence of additional stimulatory signals that further mold the nature of the T cell response. Amongst these is the ligation of CD28 on the T cell surface, a process known as “costimulation”.

In the second phase of the T cell response, which is costimulation dependent, long-lived T cells that have developed during the initial response persist for years as memory cells to protect against re-exposure to the primary insult. Recent work has revealed that these distinct phases of T cell activation are coupled to cell-intrinsic metabolic reprogramming that serves a critical role in defining T cell function and fate.

Mitochondrial flexibility is crucial for T cells

Core cellular metabolism is centered on pathways that feed nutrients into mitochondria, organelles that serve many critical functions, including the generation of energy. Mitochondria are dynamic and undergo unique structural changes that lead to functional changes in these organelles. “Metabolic reprogramming is controlled by key receptor signaling events and can be literally seen in the shapes and sizes of the T cell mitochondria,” says Erika Pearce, director at the Max Planck Institute in Freiburg. In prior studies, she and her lab linked different metabolic pathways to the morphology of mitochondria. While activated effector T cells with their high-energy demand have round and punctate mitochondria, memory T cells show a fused network of mitochondria that correlates with their lower metabolic demands.

Nevertheless, as Pearce explained: “It remained unclear what the early signaling mechanisms were that instruct mitochondrial flexibility and help T cells to appropriately adapt to metabolic demands. Understanding these issues is important, because mis-patterning of T cell metabolism is strongly associated with diseases such as autoimmunity, chronic inflammation, and cancer”.

CD28 costimulation preserves mitochondrial flexibility. Early after T cell activation, signals from CD28 prevent premature rounding of mitochondria (shown in green). The elongated mitochondria (right panels) are equipped with the capacity to generate extra energy when needed. This spare bioenergetic capacity allows T cells to cope in periods of restricted access to glucose, their preferred metabolic fuel during an effector T cell response. The elongated mitochondrial phenotype is also observed after differentiation into long-lived memory T cells. Round mitochondria (left panels) do not contain spare capacity and do not allow for development of long-lasting immune protection. — **CD28 costimulation preserves mitochondrial flexibility.** Early after T cell activation, signals from CD28 prevent premature rounding of mitochondria (shown in green). The elongated mitochondria (right panels) are equipped with the capacity to generate extra energy when needed. This spare bioenergetic capacity allows T cells to cope in periods of restricted access to glucose, their preferred metabolic fuel during an effector T cell response. The elongated mitochondrial phenotype is also observed after differentiation into long-lived memory T cells. Round mitochondria (left panels) do not contain spare capacity and do not allow for development of long-lasting immune protection.

© Pearce/Klein Geltink, MPI of Immunobiology and Epigenetics

**CD28 costimulation preserves mitochondrial flexibility.** Early after T cell activation, signals from CD28 prevent premature rounding of mitochondria (shown in green). The elongated mitochondria (right panels) are equipped with the capacity to generate extra energy when needed. This spare bioenergetic capacity allows T cells to cope in periods of restricted access to glucose, their preferred metabolic fuel during an effector T cell response. The elongated mitochondrial phenotype is also observed after differentiation into long-lived memory T cells. Round mitochondria (left panels) do not contain spare capacity and do not allow for development of long-lasting immune protection.

© Pearce/Klein Geltink, MPI of Immunobiology and Epigenetics

Pearce has developed this theme further in a paper just published by her laboratory in Cell. Ramon Klein Geltink, a postdoctoral scientist in Pearce’s laboratory, along with collaborators, show that mitochondria undergo transient changes in shape, structure, and function early following T cell activation that in many ways mimic the final mitochondrial features established in memory T cells. These changes were found to be costimulation-dependent and essential for the cells to be able to form robust memory T cells as the response progresses.

The secret to establishing functionally competent memory T cells?

“It was already known that CD28 signals during T cell activation are important for the formation of functional memory T cells that provide long-lasting protective immunity. But how this early signal, only present during activation, contributes to the functional capacity of memory T cells much later remained unknown,” explains Klein Geltink.

Based on their findings, Klein Geltink and Pearce suggest that signals emanating from CD28 ligation early in activation lead to a long lasting change in the general flexibility of mitochondria, allowing them to adapt to changing metabolic demands as the T cell response progresses. They believe that this is part of the secret to establishing long-lived T cells for immunological memory.

These new insights by the researchers of the Max Planck Institute for Immunobiology and Epigenetics in Freiburg and their colleagues may have clinical implications. Elucidating that CD28 signaling alters mitochondrial function to promote cellular longevity raises the possibility of targeting this pathway to therapeutically manipulate T cell function and fate. Pearce and Klein Geltink propose that devising therapeutic approaches to alter T cell metabolic flexibility could make the cells fitter and more robust in inhospitable microenvironments, which could confer advantages in the design of cellular immunotherapy against cancer for example. On the flip side, blunting this flexibility might improve outcomes for patients with devastating autoimmune diseases.