Nature Milestones: T cells

T cells are key players in the immune system with crucial roles during both health and disease. In this Nature Milestones we explore and celebrate pivotal studies that advanced our understanding of T cell biology. Read more.

Four seminal studies, led by one from Jacques Miller in 1961, helped identify the thymus not as a vestigial organ but as a crucial site of immune cell development. These studies paved the way for later discoveries, including the identification of T cells, how they are selected, and how they interact with other immune cells to form the complex yet delicate system required for protection from infection. Read more.

By Ching-yu Huang

In 1971, the groups of Miller and Gershon used different approaches to independently show that immunological memory resides in the T cell population. Read more.

By Zhijuan Qiu

In 1974, Doherty and Zinkernagel described the phenomenon of MHC restriction, showing that virus-specific cytotoxic T cells can only kill virus-infected target cells if they share MHC class I molecules. Read more.

By Timothy Powell

T cells have critical functions in transplant immunology and organ rejection. This milestone outlines key studies that defined the pathways of T cell allorecognition. Read more.

By Gavin Mason

Breakthrough experiments in the early 1980s led to the identification, cloning and sequencing of the elusive antigen-binding receptor on T cells. Read more.

By Alexandra Flemming

CD28, a surface molecule on T cells, was the first T cell co-stimulatory receptor to be discovered. Martin et al. and Weiss et al. independently recognized that stimulation of CD28 (then called Tp44) by agonist antibodies leads to amplified activation of T cells, but only if they are pre-stimulated through the T cell receptor complex. Antigen recognition thus requires a second signal to enable effector function. Read more.

By Ildiko Gyory

The ability to distinguish foreign tissue from one’s own is a hallmark of the adaptive immune system. In the case of T cells, this tolerance to self is established during their development in the thymus. This Milestone describes how immunological tolerance started with the simple observation of graft rejection and chimerism in cattle, to become a key physiological process characterised at the molecular level and in exquisite detail. Read more.

By Meriem Attaf

CTLA-4 and PD-1 were the first discovered and arguably the most important T cell inhibitory checkpoint molecules. Tasuku Honjo and James P. Allison were awarded a Nobel Prize in 2018 for their work understanding these molecules and leading to immune checkpoint inhibitors that have become a vital therapeutic option for patients with cancer and are now being explored as potential treatments for other diseases. Read more.

By Nick Bernard

Shimon Sakaguchi and colleagues identify CD25 as a marker that can be used to isolate and thereby finally functionally characterize regulatory T cells. Read more.

By Elizabeth Svoboda

The immunological synapse is the critical and highly ordered structure between T cells and antigen-presenting cells that is required for optimum T cell activation and function. The studies here were critical in our understanding of the formation and importance of the bullseye-like structure that forms at the immunological synapse and its role in T cell activation. Read more.

By Kirsty Minton

Studies identify the stable presence of T cells at barrier sites throughout the body. These tissue-resident memory T cells (T_RM cells) provide a rapid defence against the earliest stages of infection. Read more.

By Zoltan Fehervari

Cognate T cell–B cell interactions in germinal centres are integral to antibody responses. This function, first discovered in the late 1960s, later earned CD4⁺ T cells their well-recognized name of ‘T helper cells’. However, the subset of T cells responsible for providing help to B cells remained mostly overlooked until 2009, when research into the lineage-defining transcription factor BCL-6 provided undeniable proof of the existence of follicular helper T cells. Read more.

By Jessica McHugh

A study by Louis Picker and colleagues uses a cytomegalovirus vector vaccine to immunize macaques against highly pathogenic simian immunodeficiency virus (SIV). Over half of all animals show complete and durable protection against SIV. Importantly, vaccine efficacy is mediated by the induction of effector memory T cells and not antibodies. Subsequent studies show that the vaccines are able to progressively clear established SIV infections. Collectively, these studies emphasize the potential of T cell-directed vaccines for infectious diseases such as HIV.