T Cell Response to Chronic Infection Found to Favor Low-Affinity TCRs

Researchers from the Technical University of Munich (TUM) have provided valuable insights into the behavior of T cells, a critically important class of white blood cells, during the course of the immune response to chronic infection.

  • A Brief Overview of the T Cell Response
  • Preferential Expansion of Low-Affinity T Cell Clones During Chronic Infection
  • A New Technology: Polyclonal T Cell Transfer and Tracking System
  • Implications for T Cell-Based Immunotherapies

A Brief Overview of the T Cell Response

During a typical immune response, T cells detect and respond to infection by physically interacting with pathogen-associated molecules using proteins known as T cell receptors (TCRs). Each T cell expresses a unique TCR, and following infection, particular lineages of T cells (“clones”) are favored for rapid expansion and armament.

However, the immune system has a dilemma: while threats to survival must be quickly neutralized, the magnitude of the response and the use of resources cannot be too great, or overall stability within the body could be lost with life-threatening consequences. In the context of the T cell response, this means that only the T cells best-equipped to fight off infection should be highly activated.

Although thousands of T cell clones are present within the body, only a few dominate the immune response, such that these T cell clones may quickly produce thousands of replicates of themselves to fight off disease while other T cell lineages remain largely dormant.

During acute infection, T cells bearing TCRs that bind strongly to pathogen-associated molecules, known as antigens, are expanded preferentially. However, until recently, it was not known whether this also holds true during the later stages of chronic infections, when T cells are exposed to antigens at relatively low levels over an extended period of time.

Preferential Expansion of Low-Affinity T Cell Clones During Chronic Infection

German scientists have demonstrated that, during chronic infection with the herpesvirus cytomegalovirus (CMV), the population of expanded T cells transitions over time from clones with a high-affinity TCR to those with a low-affinity TCR.

CMV persists in the body indefinitely, transitioning between periods of activity and dormancy and occasionally re-stimulating an immune response without being eliminated completely. The virus is estimated to infect over half of humans globally and an important source of birth defects.

The study, “Reverse TCR repertoire evolution toward dominant low-affinity clones during chronic CMV Infection,” was recently published in the journal Nature Immunology by a team of immunologists from the laboratory of Professor Dr. Dirk Busch, senior author and Director of the Institute for Medical Microbiology, Immunology, and Hygiene at the TUM. Drs. Kilian Schober and Florian Voit were co-first authors of the study.

Regarding the contributions of their study to the field of immunology, Dr. Schober told ImmunoFrontiers “The most important contribution of our study is probably that we help to understand, at least a tiny bit, the underlying biology of a T cell response. However, there’s also an important contribution with regards to the development of technologies that allow us to address such biological questions in the first place.”

“We show that, during chronic antigen exposure such as CMV infection, the evolution of the T cell receptor (TCR) repertoire is not necessarily linear towards high affinity, in the sense that T cells with highest affinity TCRs are preferentially selected and continuously or increasingly dominate the entire antigen-specific T cell population. Instead, we made the unexpected observation that after an initial preferential recruitment of high affinity T cells, there is most often a “reverse” selection of T cells with low affinity during the chronic phase of infection,” Dr. Schober continued.

Their research suggested that, while the early stages of the immune response were dominated by high-affinity T cell clones, these lineages underwent molecular changes and became senescent as time passed, allowing for an expansion and numerical superiority of lower-affinity clones at later time points during chronic infection in humans and mice.

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The immunologists speculated that these findings could be attributed to either an “evolutionary compromise between host and pathogen,” intended to avoid an excessive and potentially damaging anti-CMV immune response, or a “compensatory mechanism to maintain overall population functionality,” indicating that the expansion of low-affinity cells may have occurred to prevent negative changes to the overall immune system following the senescence of the high-affinity T cell clones that dominated the early stages of infection.

A New Technology: Polyclonal T Cell Transfer and Tracking System

The team engineered a new technology to overcome an important obstacle to their research. “Physiological T cell responses are polyclonal, but it has been technologically challenging to monitor polyclonal T cell responses over time. In order to be able to monitor T cells with specific TCRs, we developed a polyclonal T cell transfer and tracking system that allows us to monitor T cell responses with single-TCR resolution,” Dr. Schober stated.

“We built up this system for the model antigen SIINFEKL of Ovalbumin, for which many different immunological models exist. This system is therefore adaptable for many different laboratories in the world. For the field of adoptive T cell therapies, it is of great significance to understand the fate of T cells that have been equipped- genetically engineered- with a specific TCR, say of defined affinity.”

“We are currently using our polyclonal T cell transfer and tracking system to understand TCR repertoire evolution in different settings, for example during an anti-tumor T cell response. For this, we have also extended the number of different TCRs that we monitor at the same time. In parallel, we are identifying TCRs also from the naive repertoire in order to understand how TCR repertoires are physiologically composed before antigen contact, and to then build up engineered polyclonal repertoires that reflect this physiology as closely as possible.”

Implications for T Cell-Based Immunotherapies

The team’s research findings and technology may influence the treatment of various chronic viral infections and cancers. Tracking and predicting the behavior and efficacy of antigen-specific T cell clones could lead to improvements in T cell-based immunotherapies such as adoptive T cell therapy, whereby T cells targeting a specific cancer antigen are harvested from the bloodstream or a tumor, grown outside the body, and re-infused into the body with the goal of stimulating an effective anti-cancer immune response.

The work has implications for the development of vaccines, such as that under development by Moderna for the prevention of cytomegalovirus infection.

“We find it particularly intriguing to speculate that polyclonal T cell responses may have a specific advantage over monoclonal T cell responses through synergistic or complementary mechanisms of TCRs with different affinities. So we’re also investigating whether this holds true, especially in the context of adoptive cell therapy,” Dr. Schober stated.

Dr. Schober’s take-home message for readers: “Investigations of T cell responses should consider polyclonality and (longitudinal) kinetics over time.”

Schober K, Voit F, Grassmann S, et al. (2020) Reverse TCR repertoire evolution toward dominant low-affinity clones during chronic CMV infection. Nature Immunology, 21, 434-441. DOI: https://doi.org/10.1038/s41590-020-0628-2