This time of year has me pretty run down, with birthdays, holidays, concerts, you name it -- all manner of good and bad stress that weighs on one’s immune system. But I never knew my T cells could get exhausted, too. Two papers from the lab of E. John Wherry, PhD, associate professor of Microbiology and director of the Institute for Immunology at Penn, have taught me otherwise.
When you get a short-lived, acute infection, such as a flu bug, the body generally responds with a coordinated response, rapidly clearing the offending pathogen. Then, their mission done, immune cells stand down, leaving a core population of cells in case of re-infection.
But what about long-term, chronic infections such as hepatitis C, HIV, and malaria? With these infections, the body and the pathogen essentially fight to a prolonged stalemate, neither able to gain an advantage. Over time, however, the battle-weary T cells become “exhausted,” giving the pathogen the edge.One paper from the Wherry lab shows just how that happens. The findings suggest a novel approach that might be used to shift the balance of power in chronic infections. The study appeared in the November 30 issue of Science. The team used a mouse model of chronic viral infection to map the T-cell response that arises when the immune system is on an extended war footing. They found that two distinct classes of virus-specific CD8+ T cells – one expressing high levels of the protein T-bet, the other expressing high levels of the protein Eomes, work together to keep the infection in check.
“Our data suggest the reason for loss of immune control during some chronic infections is that the long-term pressure on the short-term cell/long-term cell relationship depletes the short-term pool,” he says.
What’s more, the Science study suggests new therapeutic avenues that can be used to fight, or at least better control, chronic infections. For instance, Wherry suggests, “If we can maintain these progenitor cells longer, we may be able to shift the balance and maintain control of an infection.”
In a related paper in the journal Immunity, the Wherry lab defined the architecture of the genomic "network" governing the expression of genes in the exhausted CD8 T cells.
Wherry likens the network to the Internet: “The biological components of a cell are organized into nodes and hubs - Think of Google or Amazon as the hubs and everyday users as nodes in this Internet.”
Identifying hubs in the process of T-cell exhaustion allows us to define the key control points of a biological process. The team used genome-wide profiling and computational approaches to define nodes and hubs. They found that the hubs included T-bet and Eomes, the two genes/proteins described in the Science paper. But, most importantly, they found that these hubs were not connected to the same set of regulatory genes in functional T cells versus exhausted T cells.
As T cells become exhausted, the cellular circuitry that controls their function becomes massively re-wired to perform new functions.
“In the big picture, this probably provides a cell a lot more flexibility to adopt many distinct functions using a limited number of genes in the genome,” says Wherry. And perhaps, one day give us holiday-weary humans a leg up on pathogens that take advantage of the sleep deprived.
Paley MA, Kroy DC, Odorizzi PM, Johnnidis JB, Dolfi DV, Barnett BE, Bikoff EK, Robertson EJ, Lauer GM, Reiner SL, & Wherry EJ (2012). Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection. Science (New York, N.Y.), 338 (6111), 1220-5 PMID: 23197535
Doering TA, Crawford A, Angelosanto JM, Paley MA, Ziegler CG, & Wherry EJ (2012). Network Analysis Reveals Centrally Connected Genes and Pathways Involved in CD8(+) T Cell Exhaustion versus Memory. Immunity, 37 (6), 1130-44 PMID: 23159438