Table 5 Subsets related to T cell exhaustion

Progenitor or precursor exhausted T (T_PEX) cell

PD-1⁺, TOX⁺, TCF1⁺, BCL6⁺, SLAMF6⁺, CXCR3⁺, LEF1⁺, CD28⁺, CD73⁺, XCL1⁺, CXCR5⁺ (often cleaved by collagenase treatment), TIM3⁻, CD39⁻, CX₃CR1^lo/int, granzyme B⁻

See human list (left)

T_PEX cells sustain T cell responses under conditions of chronic antigenic stimulation

T_PEX cells can self-renew in response to persisting antigen and differentiate into more effector-like exhausted CD8⁺ T cells and terminally differentiated exhausted CD8⁺ T cells

Intermediate exhausted T (T_EX-int) cell, also known as effector-like exhausted T (T_EX-eff) cell

PD-1⁺, TOX⁺, TIM3⁺, T-bet⁺, granzyme B⁺, perforin⁺, IFNγ⁺, CX₃CR1⁺, TCF1⁻, SLAMF6⁻, CD101⁻

See human list (left)

When T_PEX cells proliferate in response to persisting antigen or inflammatory cues, they may give rise to these transitional exhausted CD8⁺ T cells

They express effector molecules such as granzyme B and perforin and have anti-viral and antitumour function

PD-1-directed immunotherapy enhances their generation

Terminally differentiated exhausted T (T_EX-term) cell

PD-1⁺, TOX⁺, TIM3⁺, granzyme B⁺, CD39⁺, 2B4⁺, CD101⁺, TCF1⁻, SLAMF6⁻, CX₃CR1⁻, CXCR3⁻

See human list (left)

Have little proliferative capacity and reduced and altered effector function compared to T_EX-int cells

Retain limited cytotoxicity, produce low amounts of effector cytokines, and express chemokines that help recruit other leukocytes

Can arise directly from T_PEX cells and also from T_EX-int cells

In the context of cancer, T_EX-term are often referred to as ‘dysfunctional’ T cells