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Simultaneous TCR and CD244 signals induce dynamic downmodulation of CD244 on human antiviral T cells

Yovana Pacheco1, Anna P McLean, Janine Rohrbach

  • 1Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Cambridge, MA 02139, USA.

Journal of Immunology (Baltimore, Md. : 1950)
|August 6, 2013
PubMed

Insights

CD244 (2B4) receptor internalization on T cells is triggered by dual signaling, influencing antiviral responses. This rapid process, dependent on TCR and CD244 engagement, modulates T cell function in HIV patients.

Area of Science:

  • Immunology
  • Cellular Biology
  • Virology

Background:

  • T cell activation, inhibition, and exhaustion are modulated by cosignaling molecules.
  • The SLAM family receptor CD244 (2B4) exhibits context-dependent inhibitory or enhancing effects upon CD48 engagement.
  • CD8 T cells express PD-1, CD244, and TIM-3, with altered expression in HIV(+) individuals.

Purpose of the Study:

  • To investigate the regulation and functional consequences of CD244 expression on CD8 T cells, particularly in the context of viral infections.
  • To elucidate the signaling mechanisms underlying CD244 downregulation.
  • To determine the role of CD244-CD48 interactions in modulating antiviral T cell responses.

Main Methods:

  • Analysis of CD8 T cell phenotypes from HIV(+) and HIV(neg) donors specific for HIV and/or RSV.
  • Assessment of CD244 and TIM-3 expression following superantigen or cognate peptide stimulation.
  • Utilizing pH-sensitive fluorophores to track CD244 intracellular trafficking upon TCR and CD244 signaling.
  • Investigating the involvement of PI3K signaling and PMA-ionomycin in CD244 downregulation.

Main Results:

  • Ex vivo CD8 T cells downregulated CD244 in response to superantigen.
  • Cognate peptide stimulation rapidly downregulated CD244 and TIM-3, but not PD-1, on CD8 T cell clones.
  • CD244 downmodulation required simultaneous TCR and CD244 signaling, leading to rapid internalization into acidic compartments.
  • CD244 internalization occurred rapidly after TCR stimulation and correlated with enhanced IFN-γ production upon CD48 blockade in HIV(+) subjects.

Conclusions:

  • Rapid CD244 internalization is a two-signal process involving TCR and CD244 engagement.
  • CD244 internalization plays a significant role in modulating antiviral CD8 T cell responses via CD48-CD244 signaling.
  • The degree of CD244 internalization and its functional impact may differ between HIV(+) and HIV(neg) individuals.

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