Clinical application of immune repertoire sequencing in solid organ transplant

Abstract

Background: Measurement of T cell receptor (TCR) or B cell receptor (BCR) gene utilization may be valuable in monitoring the dynamic changes in donor-reactive clonal populations following transplantation and enabling adjustment in therapy to avoid the consequences of excess immune suppression or to prevent rejection with contingent graft damage and to indicate the development of tolerance.

Objective: We performed a review of current literature to examine research in immune repertoire sequencing in organ transplantation and to assess the feasibility of this technology for clinical application in immune monitoring.

Methods: We searched MEDLINE and PubMed Central for English-language studies published between 2010 and 2021 that examined T cell/B cell repertoire dynamics upon immune activation. Manual filtering of the search results was performed based on relevancy and predefined inclusion criteria. Data were extracted based on study and methodology characteristics.

Results: Our initial search yielded 1933 articles of which 37 met the inclusion criteria; 16 of these were kidney transplant studies (43%) and 21 were other or general transplantation studies (57%). The predominant method for repertoire characterization was sequencing the CDR3 region of the TCR β chain. Repertoires of transplant recipients were found to have decreased diversity in both rejectors and non-rejectors when compared to healthy controls. Rejectors and those with opportunistic infections were more likely to have clonal expansion in T or B cell populations. Mixed lymphocyte culture followed by TCR sequencing was used in 6 studies to define an alloreactive repertoire and in specialized transplant settings to track tolerance.

Conclusion: Methodological approaches to immune repertoire sequencing are becoming established and offer considerable potential as a novel clinical tool for pre- and post-transplant immune monitoring.

Keywords: B cell receptor (BCR); T cell receptor (TCR); alloimmunity; lymphocyte receptor sequencing; solid organ transplant.

Figure 1

After antigen specific allorecognition via the antigen-specific TCR-MHC interaction (signal 1, labeled S1) second order signals are required for full T cell activation (S2 and S3). These involve engagement of immune checkpoints which are receptor-ligand pairs belonging to either the TNF or immunoglobulin superfamily. These act to either co-stimulate or co-inhibit the T cell response. Created with BioRender.com.

Figure 2

Somatic recombination of the germline DNA encoding TCR α and β chains during T cell development generates antigen-binding diversity. (A) For the TCR α chain, V-J rearrangement is followed by transcription and splicing to create a complete VJ-C mRNA. (B) For the β chain, D-J rearrangement is followed by V-DJ rearrangement, then transcription and splicing to create a complete VDJ-C mRNA. In both cases, the mRNA product is then translated to yield the protein receptor chains. The CDR3 region is the most variable portion of the TCR due to its location in the junction where V-J and V-D-J joining occurs in the α and β chains respectively. Created with BioRender.com.

Figure 3

Flow diagram for records identified, included, excluded, and reasons for exclusion.