Mapping lymphocyte lineage decisions in vivo


Mapping lymphocyte lineage decisions in vivo

Author: Dr. med. Veit Buchholz

T cell immunity is based on the expansion and differentiation of naïve antigen-specific T cell populations into short-lived effector and long-lived memory subsets. In recent years we have developed a unique approach to study the emergence of adaptive immune responses starting out from individual CD8+ T cells (Buchholz et al., 2016). Strikingly, we found that the outcome of single-cell-derived immune responses in vivo is fundamentally uncertain. In fact, we could show that a robust relationship between infectious input and immunological response is only achieved through population averaging – by cumulating the probabilistic response patterns of multiple CD8+ T cells specific to the same antigen (Buchholz et al., 2013).

Through unbiased computational modeling, we could identify the developmental framework that underlies these processes. In this framework slowly proliferating memory precursors, capable of stem cell-like self-renewal (Graef et al., 2014), differentiate into rapidly expanding but short-lived effector T cells. Recently, we have gathered compelling evidence showing that single CD4+ T cells act within a similar framework, in which T cell receptor affinity modulates their differentiation into T follicular helper, T effector or T central memory cells in a probabilistic manner (Cho et al. 2017).

In order to further extend our computational framework, we are now investigating how single T cell-derived immune responses are shaped by antigen availability and how they unfold under conditions of latent or chronic viral infection. To further extend our fate mapping capabilities, we have recently developed a fluorophore-based barcoding approach that allows highly multiplexed tracking of single T cells and other hematopoietic cell types.

 


Publications

Buchholz *, V.R., Flossdorf*, M., Hensel, I., Kretschmer, L., Weissbrich, B., Gräf, P., Verschoor, A., Schiemann, M., Höfer, T., and Busch, D.H. (2013). Disparate individual fates compose robust CD8+ T cell immunity. Science 340, 630–635. (*equal contribution)

Buchholz, V.R., Schumacher, T.N.M., and Busch, D.H. (2016). T Cell Fate at the Single-Cell Level. Annu Rev Immunol 34, 65–92.

Graef, P.*, Buchholz*, V.R., Stemberger, C., Flossdorf, M., Henkel, L., Schiemann, M., Drexler, I., Höfer, T., Riddell, S.R., and Busch, D.H. (2014). Serial transfer of single-cell-derived immunocompetence reveals stemness of CD8(+) central memory T cells. Immunity 41, 116–126. (*equal contribution)

Flossdorf M, Rössler J, Buchholz VR, Busch DH, Höfer T. (2015) CD8(+) T cell diversification by asymmetric cell division. Nat Immunol 16, 891–893.

Buchholz, V.R., Schumacher, T.N.M., and Busch, D.H. (2016). T Cell Fate at the Single- Cell Level. Annu Rev Immunol 34, 65–92.

Muschaweckh, A., Buchholz, V.R., Fellenzer, A., Hessel, C., König, P.-A., Tao, S., Tao, R., Heikenwalder, M., Busch, D.H., Korn, T., et al. (2016). Antigen-dependent competition shapes the local repertoire of tissue-resident memory CD8+ T cells. Journal of Experimental Medicine 213, 3075–3086.

Cho, Y.-L., Flossdorf, M., Kretschmer, L., Höfer, T., Busch, D.H., and Buchholz, V.R. (2017). TCR Signal Quality Modulates Fate Decisions of Single CD4(+) T Cells in a Probabilistic Manner. Cell Rep 20, 806–818.