Maintenance of the human memory T cell repertoire by subset and tissue site

Abstract

Background Immune-mediated protection is mediated by T cells expressing pathogen-specific T cell antigen receptors (TCR) that are maintained at diverse sites of infection as tissue-resident memory T cells (TRM) or that disseminate as circulating effector-memory (TEM), central memory (TCM), or terminal effector (TEMRA) subsets in blood and tissues. The relationship between circulating and tissue resident T cell subsets in humans remains elusive, and is important for promoting site-specific protective immunity. Methods We analyzed the TCR repertoire of the major memory CD4+ and CD8+T cell subsets (TEM, TCM, TEMRA, and TRM) isolated from blood and/or lymphoid organs (spleen, lymph nodes, bone marrow) and lungs of nine organ donors, and blood of three living individuals spanning five decades of life. High-throughput sequencing of the variable (V) portion of individual TCR genes for each subset, tissue, and individual were analyzed for clonal diversity, expansion and overlap between lineage, T cell subsets, and anatomic sites. TCR repertoires were further analyzed for TRBV gene usage and CDR3 edit distance. Results Across blood, lymphoid organs, and lungs, human memory, and effector CD8+T cells exhibit greater clonal expansion and distinct TRBV usage compared to CD4+T cell subsets. Extensive sharing of clones between tissues was observed for CD8+T cells; large clones specific to TEMRA cells were present in all sites, while TEM cells contained clones shared between sites and with TRM. For CD4+T cells, TEM clones exhibited the most sharing between sites, followed by TRM, while TCM clones were diverse with minimal sharing between sites and subsets. Within sites, TRM clones exhibited tissue-specific expansions, and maintained clonal diversity with age, compared to age-associated clonal expansions in circulating memory subsets. Edit distance analysis revealed tissue-specific biases in clonal similarity. Conclusions Our results show that the human memory T cell repertoire comprises clones which persist across sites and subsets, along with clones that are more restricted to certain subsets and/or tissue sites. We also provide evidence that the tissue plays a key role in maintaining memory T cells over age, bolstering the rationale for site-specific targeting of memory reservoirs in vaccines and immunotherapies.

Anti-TRBC1 Antibody-Based Flow Cytometric Detection of T-Cell Clonality: Standardization of Sample Preparation and Diagnostic Implementation

“…Thus, the overall normal TRBC1 + /TRBC1 − ratio ranges of naïve, central memory, transitional memory and regulatory Tαβ-cell subsets overlapped with those of the whole Tαβ-cell populations and/or their major TαβCD4 + and TαβCD8 + subsets, whereas more mature populations of CD28 + and particularly CD28effector memory, early effector, and terminal effector cells of HD displayed more heterogeneous and clear skewed TRBC1 + /TRBC1 − ratios compared with those of total Tαβ-cells, regardless of the specific subset of, for example, TαβCD4 + or TαβCD8 + cells. These findings support an increasingly higher degree of oligoclonality associated with a progressively narrower TR repertoire, along the maturation of blood Tαβ-cells, due to the accumulation of effector T-cells specific for a relatively more limited number of antigens, including antigens from viruses that persist in the organism, such as EBV and cytomegalovirus [46]. The fact that the TRBC1 + /TRBC1 − ratio of more mature Tαβ-cell populations usually deviates from those of total Tαβ-cells from the same subject should be considered in the diagnostic work-up of T-cell clonality by FCM, particularly in the absence of phenotypic aberrations and when suspicious effector (e.g., LGL) Tαβcell populations are investigated.…”

HIV rapidly targets a diverse pool of CD4+ T cells to establish productive and latent infections

“…The fact that HIV preferentially infects cells belonging to large clones ( 44 ) that recirculate between blood and tissues is consistent with the preferential infection of effector memory CD4+ T cells during acute infection, as we previously reported ( 8, 45 ). Indeed, when compared to less differentiated central memory cells, effector memory cells are known to display restricted TCR repertoire as a result of their expansions ( 46, 47 ), to contain clones shared between anatomical sites ( 48 ), and to express higher levels of CCR5.…”

Two Step Selection for Bias in β Chain V-J Pairing

“…The dataset contains four CD4+ and CD8+ T cell types: TCM (CD45RA-CCR7+), TEM (CD45RA-CCR7-CD69-), TRM (CD45RA-CCR7-CD69+), and TEMRA (CD45RA+ CCR7-) cells. (See Miron et al (26) for details.) • The Emerson dataset.…”