TIM3 is a context-­ dependent coregulator of cytotoxic T cell function

Hanin I A Alamir; Carissa C W Wong; Amal A Alsubaiti; Grace L Edmunds; Maryam Alismail; Lan T L Huynh; Yiwei Shi; Philip A Lewis; Tressan Grant; Safaa A S Alsulaimani; James R Boyd; Christopher J Holland; David J Morgan; Awen M Gallimore; Christoph Wuelfing

doi:10.1126/scisignal.adk4594

TIM3 is a context- dependent coregulator of cytotoxic T cell function

Hanin I A Alamir
, Carissa C W Wong
, Amal A Alsubaiti
, Grace L Edmunds
, Maryam Alismail
, Lan T L Huynh
, Yiwei Shi
, Philip A Lewis
, Tressan Grant
, Safaa A S Alsulaimani
, James R Boyd
, Christopher J Holland
, David J Morgan
, Awen M Gallimore
, Christoph Wuelfing^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

2 Citations (Scopus)

76 Downloads (Pure)

Abstract

TIM3 is a coregulatory receptor that is highly abundant on multiple immune cell types, including T cells in response to prolonged exposure to antigen, and it marks functionally suppressed cytotoxic T lymphocytes (CTLs) in the tumor microenvironment. TIM3 exhibits inhibitory function in vivo but paradoxically has costimulatory T cell signaling capability in vitro. Here, we found that TIM3 directly inhibited the function of murine and human CTLs in direct interaction with target tumor cell spheroids. TIM3 regulated the ability of suppressed CTLs to polarize their actin cytoskeleton as a required step in cytolysis. Whereas the expression of the proposed TIM3 ligands CEACAM1 and galectin 9 in trans on target tumor cells enhanced TIM3 function, expression of CEACAM1 in cis on CTLs had the opposite effect. TIM3 functioned as an inhibitory receptor on spheroid- suppressed CTLs but not on active CTLs in a two- dimensional tissue culture model. Together, these data suggest that TIM3 enhances T cell function, serving as either a coinhibitory or costimulatory receptor depending on the functional context of the T cell on which it is expressed.

Original language	English
Article number	eadk4594
Pages (from-to)	eadk4594
Number of pages	21
Journal	Science Signaling
Volume	18
Issue number	905
DOIs	https://doi.org/10.1126/scisignal.adk4594
Publication status	Published - 23 Sept 2025

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© 2025 The Authors, some rights reserved;.

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This is the accepted author manuscript (AAM) of the article which has been made Open Access under the University of Bristol's Scholarly Works Policy. The final published version (Version of Record) can be found on the publisher's website. The copyright of any third-party content, such as images, remains with the copyright holder.
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Alamir, H. I. A., Wong, C. C. W., Alsubaiti, A. A., Edmunds, G. L., Alismail, M., Huynh, L. T. L., Shi, Y., Lewis, P. A., Grant, T., Alsulaimani, S. A. S., Boyd, J. R., Holland, C. J., Morgan, D. J., Gallimore, A. M., & Wuelfing, C. (2025). TIM3 is a context- dependent coregulator of cytotoxic T cell function. Science Signaling, 18(905), eadk4594. Article eadk4594. https://doi.org/10.1126/scisignal.adk4594

@article{b1f42848a76141da8fda1a27d67fb4e7,

title = "TIM3 is a context- dependent coregulator of cytotoxic T cell function",

abstract = "TIM3 is a coregulatory receptor that is highly abundant on multiple immune cell types, including T cells in response to prolonged exposure to antigen, and it marks functionally suppressed cytotoxic T lymphocytes (CTLs) in the tumor microenvironment. TIM3 exhibits inhibitory function in vivo but paradoxically has costimulatory T cell signaling capability in vitro. Here, we found that TIM3 directly inhibited the function of murine and human CTLs in direct interaction with target tumor cell spheroids. TIM3 regulated the ability of suppressed CTLs to polarize their actin cytoskeleton as a required step in cytolysis. Whereas the expression of the proposed TIM3 ligands CEACAM1 and galectin 9 in trans on target tumor cells enhanced TIM3 function, expression of CEACAM1 in cis on CTLs had the opposite effect. TIM3 functioned as an inhibitory receptor on spheroid- suppressed CTLs but not on active CTLs in a two- dimensional tissue culture model. Together, these data suggest that TIM3 enhances T cell function, serving as either a coinhibitory or costimulatory receptor depending on the functional context of the T cell on which it is expressed.",

author = "Alamir, \{Hanin I A\} and Wong, \{Carissa C W\} and Alsubaiti, \{Amal A\} and Edmunds, \{Grace L\} and Maryam Alismail and Huynh, \{Lan T L\} and Yiwei Shi and Lewis, \{Philip A\} and Tressan Grant and Alsulaimani, \{Safaa A S\} and Boyd, \{James R\} and Holland, \{Christopher J\} and Morgan, \{David J\} and Gallimore, \{Awen M\} and Christoph Wuelfing",

note = "Publisher Copyright: {\textcopyright} 2025 The Authors, some rights reserved;.",

year = "2025",

month = sep,

day = "23",

doi = "10.1126/scisignal.adk4594",

language = "English",

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Alamir, HIA, Wong, CCW, Alsubaiti, AA, Edmunds, GL, Alismail, M , Huynh, LTL , Shi, Y, Lewis, PA, Grant, T, Alsulaimani, SAS , Boyd, JR, Holland, CJ, Morgan, DJ, Gallimore, AM & Wuelfing, C 2025, 'TIM3 is a context- dependent coregulator of cytotoxic T cell function', Science Signaling, vol. 18, no. 905, eadk4594, pp. eadk4594. https://doi.org/10.1126/scisignal.adk4594

TY - JOUR

T1 - TIM3 is a context- dependent coregulator of cytotoxic T cell function

AU - Alamir, Hanin I A

AU - Wong, Carissa C W

AU - Alsubaiti, Amal A

AU - Edmunds, Grace L

AU - Alismail, Maryam

AU - Huynh, Lan T L

AU - Shi, Yiwei

AU - Lewis, Philip A

AU - Grant, Tressan

AU - Alsulaimani, Safaa A S

AU - Boyd, James R

AU - Holland, Christopher J

AU - Morgan, David J

AU - Gallimore, Awen M

AU - Wuelfing, Christoph

PY - 2025/9/23

Y1 - 2025/9/23

N2 - TIM3 is a coregulatory receptor that is highly abundant on multiple immune cell types, including T cells in response to prolonged exposure to antigen, and it marks functionally suppressed cytotoxic T lymphocytes (CTLs) in the tumor microenvironment. TIM3 exhibits inhibitory function in vivo but paradoxically has costimulatory T cell signaling capability in vitro. Here, we found that TIM3 directly inhibited the function of murine and human CTLs in direct interaction with target tumor cell spheroids. TIM3 regulated the ability of suppressed CTLs to polarize their actin cytoskeleton as a required step in cytolysis. Whereas the expression of the proposed TIM3 ligands CEACAM1 and galectin 9 in trans on target tumor cells enhanced TIM3 function, expression of CEACAM1 in cis on CTLs had the opposite effect. TIM3 functioned as an inhibitory receptor on spheroid- suppressed CTLs but not on active CTLs in a two- dimensional tissue culture model. Together, these data suggest that TIM3 enhances T cell function, serving as either a coinhibitory or costimulatory receptor depending on the functional context of the T cell on which it is expressed.

AB - TIM3 is a coregulatory receptor that is highly abundant on multiple immune cell types, including T cells in response to prolonged exposure to antigen, and it marks functionally suppressed cytotoxic T lymphocytes (CTLs) in the tumor microenvironment. TIM3 exhibits inhibitory function in vivo but paradoxically has costimulatory T cell signaling capability in vitro. Here, we found that TIM3 directly inhibited the function of murine and human CTLs in direct interaction with target tumor cell spheroids. TIM3 regulated the ability of suppressed CTLs to polarize their actin cytoskeleton as a required step in cytolysis. Whereas the expression of the proposed TIM3 ligands CEACAM1 and galectin 9 in trans on target tumor cells enhanced TIM3 function, expression of CEACAM1 in cis on CTLs had the opposite effect. TIM3 functioned as an inhibitory receptor on spheroid- suppressed CTLs but not on active CTLs in a two- dimensional tissue culture model. Together, these data suggest that TIM3 enhances T cell function, serving as either a coinhibitory or costimulatory receptor depending on the functional context of the T cell on which it is expressed.

U2 - 10.1126/scisignal.adk4594

DO - 10.1126/scisignal.adk4594

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SP - eadk4594

JO - Science Signaling

JF - Science Signaling

IS - 905

M1 - eadk4594

ER -