In View: Research Highlights
Induction and Transcriptional Regulation of the Co-inhibitory Gene Module in T Cells
Chihara N, Madi A, Kondo T, et al. Nature. 2018;558:454-459.
The maintenance of immune homeostasis requires that robust responses to pathogens and tumors do not compromise tolerance to self-antigens. Several mechanisms exist that limit immune responses with one of the most significant being the expression of lymphocyte coinhibitory molecules that prevent cellular activation and subsequent effector activity.1 Tumors exploit these endogenous inhibitory mechanisms to evade immune clearance and “paralyze” the immune response against the tumor. There is therefore increasing interest in “checkpoint” inhibitors that target lymphocyte coinhibitory molecules to promote antitumor responses. The most common checkpoint inhibitors target PD-1, its ligand, and CTLA-4.2 Although therapeutic goals in transplantation and cancer immunology are diametrically opposite (with 1 field aiming to promote tolerance and the other aiming to abrogate it), knowledge from cancer immunology is of great relevance to transplantation, particularly for the appreciation of costimulatory blockade in organ transplantation. In the June issue of Nature, Chihara and coworkers examined tumor-infiltrating lymphocytes using single cell RNA and protein expression analyses.3 Interestingly, both CD4+ and CD8+ cells expressed coinhibitory molecules as a collection, or “module.” These included known coinhibitory molecules, such as PD-1, TIM-3, and LAG-3, but also some new receptors validated by the authors: activated protein C receptor and podoplanin. Interestingly, IL-27 was the common factor that led to the induction of a gene program comprising these co-inhibitory receptors resulting in T cell dysfunction and tolerance. In their study, the transcription factor PR Domain-Containing Protein 1 was identified as a regulator of the coinhibitory program. The knockout of this molecule in T cells resulted in a reduced expression of the group of coinhibitory receptors and enhanced tumor clearance in a mouse model.
This is a landmark study for our understanding of T cell biology with important implications for transplantation. The identification of new coinhibitory receptors and an in-depth understanding of mechanisms involved provide valuable and novel therapeutic opportunities.
- Vinay DS, Ryan EP, Pawelec G, et al. Immune evasion in cancer: mechanistic basis and therapeutic strategies. Semin Cancer Biol. 2015;35(Suppl):S185–S198.
- Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018;359:1350–1355.
- Chihara N, Madi A, Kondo T, et al. Induction and transcriptional regulation of the co-inhibitory gene module in T cells. Nature. 2018;558:454–459
Lymphoid Tissue Fibrosis is Associated with Impaired Vaccine Responses
Kityo C, Makamdop KN, Rothenberger M, et al. J Clin Invest. [published online May 21, 2018]. doi:10.1172/JCI97377.
Vaccine immune responses are impaired after transplantation, making normally preventable infections a significant challenge posttransplantation. Pretransplantation vaccination is therefore the standard recommendation, with serology analysis after vaccination to assess for efficacy, where possible. Although there is a major effort to understand vaccine efficacy and the causes for poor responses in certain patients, challenges are prevalent and are not restricted solely to the transplant population. There is, for example, a geographical variation, with some vaccines showing enhanced responses according to latitude or continent. Several mechanisms have been proposed, including differences in immune constitution (eg, regulatory T cell levels) and the presence of endemic infections that may alter the potency of induced responses. Human immunodeficiency virus–associated lymph node (LN) fibrosis has previously been shown to be responsible for loss of T cells and blunted immune responses. In the study by Kityo and coworkers,1 LN fibrosis was shown to also result in reduced vaccine responses in the absence of human immunodeficiency virus. Lymph node samples and vaccine responses were compared in people from Uganda and the United States, before and after yellow fever vaccination. Before vaccination, there was increased T-cell zone fibrosis in people from Uganda. The degree of fibrosis correlated to blunted antibody responses after yellow fever vaccination. This preexisting LN pathology likely restricts the development of antibody responses and, importantly, existed in otherwise healthy Ugandans. The authors suggest that the LN pathology may be related to previous endemic infections, such as malaria, salmonella, and tuberculosis. It is possible, however, that the changes are related to other undefined elements such as genetic or environmental factors. This work highlights important challenges that are generally not accounted for when vaccinating transplant recipients. Future studies may help to identify biomarkers of poor responses in patients that would help alter vaccination strategies. Additionally, it will be interesting to evaluate whether poor vaccination responses are also related to blunted alloresponses. For further specific information about vaccination in solid-organ transplant recipients, a useful set of recommendations has recently been published in Transplantation.2
- Kityo C, Makamdop KN, Rothenberger M, et al. Lymphoid tissue fibrosis is associated with impaired vaccine responses. J Clin Invest. [published online May 21, 2018]. doi:10.1172/JCI97377.
- Stucchi RSB, Lopes MH, Kumar D, et al. Vaccine recommendations for solid-organ transplant recipients and donors. Transplantation. 2018;102(2S Suppl 2):S72–S80.