Bcl-2 allows effector and memory CD8+ T cells to tolerate higher expression of Bim

J Immunol. 2011 May 15;186(10):5729-37. doi: 10.4049/jimmunol.1100102. Epub 2011 Mar 30.

Abstract

As acute infections resolve, most effector CD8(+) T cells die, whereas some persist and become memory T cells. Recent work showed that subsets of effector CD8(+) T cells, identified by reciprocal expression of killer cell lectin-like receptor G1 (KLRG1) and CD127, have different lifespans. Similar to previous reports, we found that effector CD8(+) T cells reported to have a longer lifespan (i.e., KLRG1(low)CD127(high)) have increased levels of Bcl-2 compared with their shorter-lived KLRG1(high)CD127(low) counterparts. Surprisingly, we found that these effector KLRG1(low)CD127(high) CD8(+) T cells also had increased levels of Bim compared with KLRG1(high)CD127(low) cells. Similar effects were observed in memory cells, in which CD8(+) central memory T cells expressed higher levels of Bim and Bcl-2 than did CD8(+) effector memory T cells. Using both pharmacologic and genetic approaches, we found that survival of both subsets of effector and memory CD8(+) T cells required Bcl-2 to combat the proapoptotic activity of Bim. Interestingly, inhibition or absence of Bcl-2 led to significantly decreased expression of Bim in surviving effector and memory T cells. In addition, manipulation of Bcl-2 levels by IL-7 or IL-15 also affected expression of Bim in effector CD8(+) T cells. Finally, we found that Bim levels were significantly increased in effector CD8(+) T cells lacking Bax and Bak. Together, these data indicate that cells having the highest levels of Bim are selected against during contraction of the response and that Bcl-2 determines the level of Bim that effector and memory T cells can tolerate.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Bcl-2-Like Protein 11
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Survival
  • Genes, bcl-2
  • Immunologic Memory*
  • Interleukin-15 / immunology
  • Interleukin-15 / metabolism
  • Interleukin-7 / immunology
  • Interleukin-7 / metabolism
  • Interleukin-7 Receptor alpha Subunit / genetics
  • Interleukin-7 Receptor alpha Subunit / immunology
  • Lectins, C-Type
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Polymerase Chain Reaction
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / immunology
  • T-Lymphocyte Subsets / immunology*
  • bcl-2 Homologous Antagonist-Killer Protein / deficiency
  • bcl-2 Homologous Antagonist-Killer Protein / genetics
  • bcl-2-Associated X Protein / deficiency
  • bcl-2-Associated X Protein / genetics

Substances

  • Apoptosis Regulatory Proteins
  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, mouse
  • Interleukin-15
  • Interleukin-7
  • Interleukin-7 Receptor alpha Subunit
  • Klrg1 protein, mouse
  • Lectins, C-Type
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Immunologic
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein