Unique features and clinical importance of acute alloreactive immune responses
Charlotte F. Inman, … , Ram Malladi, Paul Moss
Charlotte F. Inman, … , Ram Malladi, Paul Moss
Published May 17, 2018
Citation Information: JCI Insight. 2018;3(10):e97219. https://doi.org/10.1172/jci.insight.97219.
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Research Article Hematology Immunology

Unique features and clinical importance of acute alloreactive immune responses

Abstract

Allogeneic stem cell transplantation (allo-SCT) can cure some patients with hematopoietic malignancy, but this relies on the development of a donor T cell alloreactive immune response. T cell activity in the first 2 weeks after allo-SCT is crucial in determining outcome, despite the clinical effects of the early alloreactive immune response often not appearing until later. However, the effect of the allogeneic environment on T cells is difficult to study at this time point due to the effects of profound lymphopenia. We approached this problem by comparing T cells at week 2 after allograft to T cells from autograft patients. Allograft T cells were present in small numbers but displayed intense proliferation with spontaneous cytokine production. Oligoclonal expansions at week 2 came to represent a substantial fraction of the established T cell pool and were recruited into tissues affected by graft-versus-host disease. Transcriptional analysis uncovered a range of potential targets for immune manipulation, including OX40L, TWEAK, and CD70. These findings reveal that recognition of alloantigen drives naive T cells toward a unique phenotype. Moreover, they demonstrate that early clonal T cell responses are recruited to sites of subsequent tissue damage and provide a range of targets for potential therapeutic immunomodulation.

Authors

Charlotte F. Inman, Suzy A. Eldershaw, Joanne E. Croudace, Nathaniel J. Davies, Archana Sharma-Oates, Tanuja Rai, Hayden Pearce, Mirjana Sirovica, Y.L. Tracey Chan, Kriti Verma, Jianmin Zuo, Sandeep Nagra, Francesca Kinsella, Jane Nunnick, Rasoul Amel-Kashipaz, Charles Craddock, Ram Malladi, Paul Moss

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Figure 3

Week 2 T cells from allograft patients have a highly proliferative and activated phenotype.

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Week 2 T cells from allograft patients have a highly proliferative and a...
(A) Mean Ki-67 expression by T cells at week 2 after allo-SCT (n = 13) and auto-SCT (n = 10) and, for comparison, healthy donors (HDs; n = 9). Error bars represent the SEM; data were analyzed by a 1-way ANOVA with a Tukey’s multiple comparisons test, ****P < 0.0001. (B) Expression of CD25 and CD69 by T cells at week 2 after allo-SCT (n = 7) and week 2 after auto-SCT (n = 5) and that in healthy donors (HDs; n = 5) on naive, CM, EM, and EMRA subsets. Data were analyzed using a Kruskal-Wallis test with a Dunn’s multiple comparisons test, *P < 0.05, **P < 0.01. (C) Representative FACS plots showing constitutive (i.e., without mitogenic stimulation) IFN-γ and TNF-α production (dot plots) and CD107a expression (histograms) by CD4 and CD8 week 2 T cells from an allograft patient (Allo). Representative plots from an autograft patient (Auto) are shown for comparison. (D) Expression of IFN-γ, TNF-α, and CD107a by CD4 week 2 T cells from allograft patients (n = 9), autograft patients (n = 5), and HDs (n = 4). Data were analyzed by a Kruskal-Wallis test with a Dunn’s multiple comparisons test, *P < 0.05, **P < 0.01. Polyfunctionality plots showing number of functions exhibited by CD4 T cells from each allograft, autograft, and healthy donor. Each pie chart represents 1 individual. (E) Expression of IFN-γ, TNF-α, and CD107a by CD8 week 2 T cells from allograft patients (n = 9), autograft patients (n = 5), and HDs (n = 4). Data were analyzed by a Kruskal-Wallis test with a Dunn’s multiple comparisons test, *P < 0.05; **P < 0.01. Polyfunctionality plots showing number of functions exhibited by CD8 T cells from each allograft, autograft, and healthy donor. Each pie chart represents 1 individual.