Alloimmune T cells in transplantation

Abstract

Alloimmune T cells are central mediators of rejection and graft-versus-host disease in both solid organ and hematopoietic stem cell transplantation. Unique among immune responses in terms of its strength and diversity, the T cell alloresponse reflects extensive genetic polymorphisms between allogeneic donors and recipients, most prominently within the major histocompatibility complex (MHC), which encodes human leukocyte antigens (HLAs) in humans. The repertoire of alloreactive T cell clones is distinct for every donor-recipient pair and includes potentially thousands of unique HLA/peptide specificities. The extraordinary magnitude of the primary alloresponse and diversity of the T cell population mediating it have presented technical challenges to its study in humans. High-throughput T cell receptor sequencing approaches have opened up new possibilities for tackling many fundamental questions about this important immunologic phenomenon.

Figure 1. Pathways of allorecognition.

Schematic illustration of the three major pathways of allorecognition: direct, indirect, and semidirect. In the direct pathway, donor antigen-presenting cells (APCs) interact directly with recipient T cells. In indirect recognition, recipient APCs present processed donor allogeneic peptides to recipient T cells, similar to more typical immune responses. In the semidirect pathway, recipient APCs acquire donor HLA molecules that present peptides directly to recipient T cells.

Figure 2. Defining a “fingerprint” of the alloresponse via TCR sequencing.

From peripheral donor and recipient blood, unstimulated T cells and alloreactive T cells, isolated via FACS of CFSE-low cells in a recipient antidonor MLR, undergo high-throughput TCRβ CDR3 sequencing. Computational processing enables definition of a “fingerprint” of the alloreactive T cell population for any potential donor-recipient pair.