Tracking T cells
The infiltration of T cells into tumors is considered beneficial for the rejection of malignantly transformed cells. In particular, cytotoxic T lymphocytes (CTLs) are thought to destroy tumor cells and secrete cytokines that activate other effector T cell populations; however, recent evidence suggests that many infiltrating tumor-reactive CTLs are dysfunctional and exhibit features common in T cell exhaustion. Christian Bauer, Edward Kim, and colleagues at Harvard Medical School developed a murine model of adoptive T cell therapy to track T cell populations within tumor tissue. Using this model, the authors determined that regulatory T cells (Tregs) mediate the induction of an exhaustion-like phenotype in tumor-specific CTLs that corresponds with impaired cytotoxicity and cytokine release. Tumor antigen-specific Tregs were initially activated in the draining lymph node, where they expanded prior to migrating to the tumor. Within tumors, Tregs interacted with antigen presenting cells (APCs), decreasing expression of co-stimulatory molecules on the APC surface. The interaction of Treg-modulated APCs with tumor CLTs directly suppressed CTL function, resulting in upregulation of the co-inhibitory molecules PD1 and TIM3. The accompanying multiphoton intravital microscopy image shows CTLs (green) at the border between tumor parenchyma (blue) and stroma. The tumor vasculature (red) was labeled by i.v. injection of quantum dots.
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Abstract
Tregs control various functions of effector T cells; however, where and how Tregs exert their immunomodulatory effects remain poorly understood. Here we developed a murine model of adoptive T cell therapy and found that Tregs induce a dysfunctional state in tumor-infiltrating CTLs that resembles T cell exhaustion and is characterized by low expression of effector cytokines, inefficient cytotoxic granule release, and coexpression of coinhibitory receptors PD-1 and TIM-3. Induction of CTL dysfunction was an active process, requiring local TCR signals in tumor tissue. Tregs infiltrated tumors only subsequent to Ag-dependent activation and expansion in tumor-draining LNs; however, Tregs also required local Ag reencounter within tumor tissue to induce CTL dysfunction and prevent tumor rejection. Multiphoton intravital microscopy revealed that in contrast to CTLs, Tregs only rarely and briefly interrupted their migration in tumor tissue in an Ag-dependent manner and formed unstable tethering-interactions with CD11c+ APCs, coinciding with a marked reduction of CD80 and CD86 on APCs. Activation of CTLs by Treg-conditioned CD80/86lo DCs promoted enhanced expression of both TIM-3 and PD-1. Based on these data, we propose that Tregs locally change the costimulatory landscape in tumor tissue through transient, Ag-dependent interactions with APCs, thus inducing CTL dysfunction by altering the balance of costimulatory and coinhibitory signals these cells receive.
Authors
Christian A. Bauer, Edward Y. Kim, Francesco Marangoni, Esteban Carrizosa, Natalie M. Claudio, Thorsten R. Mempel
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ISSN: 0021-9738 (print), 1558-8238 (online)