Gamma-delta T lymphocytes

Development and migration of γδ T lymphocytes

The development of γδ T cells begins in the embryonic period and occurs in waves. In mice, this process has been studied best:

• The first wave starts on day 14 of embryogenesis. The cells form in the thymus (with TCR Vγ5Jγ1Cγ1/Vδ1Dδ2Jδ2Cδ) and migrate predominantly to the epidermis.
• The second wave occurs almost simultaneously with the first. Cells with an altered TCR composition (Vγ6Jγ1Cγ1/Vδ1Dδ2Jδ2Cδ) head to the epithelium of the female reproductive system and the tongue epithelium.
• Late embryonic and early postnatal periods are characterized by the appearance of a more diverse spectrum of TCRs (γ-chains of the Vγ1, Vγ2, Vγ4, Vγ7 families in combination with Vδ2). These lymphocytes populate the intestinal mucosa and lymphoid organs.

Interestingly, after birth, γδ T cells account for only about 1% of developing thymocytes. They do not undergo the complex selection process in the thymus and therefore leave it very quickly.

Localization and chemokine receptors

The distribution of γδ T cells has species-specific features, but a general rule is their accumulation in barrier tissues. In humans, they are scarce in the peripheral blood (about 5%), while the bulk are concentrated in the mucous membranes of the respiratory tract, intestines, and the epidermis.

Precise cell migration to the required tissues is ensured by specific chemokine receptors:

• CCR9 — responsible for migration to the small intestine.
• CCR4 and CCR10 — direct cells to the skin and lungs.
• CCR5 — is present on the majority of blood γδ T cells and attracts them to sites of inflammation.
• CCR7 — appears on mucosal cells only upon activation, directing them to the T-zones of lymphoid organs.

Antigen-recognizing capacity and functions

The antigen-recognizing receptor (γδ TCR) has limited variability, yet is capable of recognizing diverse targets:

• Non-classic MHC molecules (T10/T22) without peptide presentation.
• Microbial phosphoproteins (containing isopentenyl pyrophosphates).
• Stress molecules (MIC) via NKG2D and NKG2/CD94 receptors (similar to NK cells).
• Pathogen patterns via TLR-1 and TLR-3.

Most γδ T cells lack CD4 and CD8 coreceptors, allowing them to recognize antigens independently of classic MHC molecules. Activation occurs without costimulatory molecules.

Four main functions of γδ T cells:

1. Cytotoxic: destruction of pathogens in the first line of defense.
2. Regulatory: suppression of autoaggression and excessive immune response.
3. Antigen-presenting: the ability to act as professional APCs in lymph nodes.
4. Barrier maintenance: interaction with the epithelium, stimulation of its regeneration and survival.

Intestinal CD8αα T cell subpopulation

In the mucosa of the small intestine, up to 60% of γδ T cells carry the CD8αα homodimer on their surface (in the large intestine, they are less than 5%). These cells possess a number of unique properties:

• Origin: Their precursors likely undergo gene rearrangement in the thymus and then migrate to the intestine (with the help of CD122 and CCR9), where their maturation may be completed.
• TCR features: Instead of the standard $\zeta_2$ dimer, they contain an Fc$\varepsilon$RI$\gamma$ homodimer or a $\zeta$ / Fc$\varepsilon$RI$\gamma$ heterodimer.
• CD8αα function: Not a classic coreceptor, since antigen recognition is restricted to non-classic MHC-I molecules.
• Role: Combine the properties of effector and regulatory cells. Participate in homeostasis under the control of interleukin-15 (IL-15), recognize stress molecules (MICA/B), and harbor autoreactive clones.

Class and exam questions

What else to study on this topic

• Structure and genetics of γδ TCR
• Comparison of γδ T cells with classic αβ T lymphocytes
• Role of γδ T cells in antitumor immunity
• Interaction of γδ T cells with dendritic cells

Other topics in the "Adaptive Immunity" section

Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.